DE102005005446A1 - Unbreakable dosage forms with delayed release - Google Patents
Unbreakable dosage forms with delayed releaseInfo
- Publication number
- DE102005005446A1 DE102005005446A1 DE102005005446A DE102005005446A DE102005005446A1 DE 102005005446 A1 DE102005005446 A1 DE 102005005446A1 DE 102005005446 A DE102005005446 A DE 102005005446A DE 102005005446 A DE102005005446 A DE 102005005446A DE 102005005446 A1 DE102005005446 A1 DE 102005005446A1
- Authority
- DE
- Germany
- Prior art keywords
- dosage form
- preferably
- characterized
- agents
- form according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
Die Erfindung betrifft eine Darreichungsform, umfassend eine physiologisch wirksame Substanz (A) mit zumindest teilweise retardierter Freisetzung; The invention relates to a dosage form comprising a physiologically active substance (A) with at least partially retarded release; gegebenenfalls einen oder mehrere physiologisch verträgliche Hilfsstoffe (B); optionally one or more physiologically acceptable auxiliary substances (B); und ein synthetisches oder natürliches Polymer (C); and a synthetic or natural polymer (C); wobei die Darreichungsform eine Bruchfestigkeit von mindestens 400 N aufweist. wherein the dosage form exhibits a breaking strength of at least 400 N.
Description
- Die vorliegende Erfindung betrifft eine Darreichungsform zur Verabreichung einer physiologisch wirksamen Substanz (A), wobei die Darreichungsform mechanisch stabilisiert ist, so dass sie mit herkömmlichen Methoden, wie Hämmern, Mahlen, Mörsern, etc., nicht, oder zumindest nur sehr schwierig zerkleinert werden kann. The present invention relates to a dosage form for administering a physiologically active substance (A), wherein the dosage form is mechanically stabilized, so that it can be crushed very difficult with conventional methods, such as hammers, milling, mortars, etc., do not, or at least , Die Substanz (A) wird aus der erfindungsgemäßen Darreichungsform unter physiologischen Bedingungen mit einem zumindest teilweise retardierten Profil freigesetzt. The substance (A) is released from the dosage form according to the invention under physiological conditions with an at least partially retarded profile.
- Zahlreiche physiologisch wirksame Substanzen, wie Nahrungsergänzungsmittel, Arzneistoffe, etc. werden als Retard-Formulierungen bereitgestellt, dh im Gegensatz zu herkömmlichen Formulierungen (zB sog. "immediate release" Formulierungen) werden die Substanzen aus diesen Formulierungen verzögert über eine vergleichsweise lange Zeitspanne, die oft mehrere Stunden beträgt, an den Organismus abgegeben. Many physiologically active substances, such as food supplements, drugs, etc. are provided as sustained release formulations, that is in contrast to conventional formulations (eg so-called. "Immediate release" formulations), the substances from these formulations delayed over a comparatively long period of time, often is several hours, delivered to the body. Die Freisetzung der Substanz aus der Darreichungsform einerseits und eine Metabolisierung bzw. Ausscheidung durch den Organismus andererseits gewährleisten einen relativ gleichmäßigen Blutplasmaspiegel der verabreichten Substanz. The release of the substance from the dosage form on the one hand and a metabolism and excretion by the body on the other hand ensure a relatively uniform blood plasma level of the administered substance. Als eine Folge davon kann häufig für den Patienten die Anzahl der pro Tag einzunehmenden Dosiseinheiten reduziert werden, oft ist eine Einnahme nur noch ein- oder zweimal am Tag erforderlich. As a result, the number of taken per day dosage units can be reduced frequently to the patient intake often being only once or twice a day required.
- Retard-Formulierungen können in bestimmten Fällen auch das Ausmaß an Nebenwirkungen der Substanz vermindern. Sustained-release formulations may also reduce the extent of side effects of the substance in certain cases. So treten zB bei einigen Arzneistoffen verstärkt Nebenwirkungen auf, wenn im Blutplasma zumindest vorübergehend eine bestimmte Grenzkonzentration des Arzneistoffs überschritten wird. So for example, some drugs more adverse reactions when at least temporarily a certain threshold concentration of the drug is exceeded in blood plasma. Derartige Arzneistoffe sind daher für "immediate release" Formulierungen weitgehend ungeeignet, insbesondere wenn eine nur zwei- oder dreimalige tägliche Verabreichung erwünscht ist. Such drugs are thus largely unsuitable for "immediate release" formulations, in particular when only two or three times daily administration is desired. Solche Arzneistoffe werden daher üblicherweise als Retard-Formulierungen verabreicht, wodurch eine kontinuierliche Freisetzung des Wirkstoffs gewährleistet und das kurzfristige Auftreten hoher Konzentrationen verhindert werden. Such drugs are therefore typically administered as sustained-release formulations, thus ensuring a continuous release of the active substance and the short-term exposure to high concentrations are prevented.
- Bei Retard-Formulierungen ist üblicherweise die physiologisch wirksame Substanz entweder in einer die Freisetzung steuernden Matrix eingebettet, und/oder die Darreichungsform ist mit einem Film überzogen, welcher die Freisetzung steuert. When sustained-release formulations of the physiologically active substance either in a release is typically controlled matrix embedded and / or the dosage form is coated with a film which controls the release.
- Insbesondere ältere Patienten haben jedoch häufig Schwierigkeiten beim Einnehmen fester Darreichungsformen, wie Tabletten, Gelatinekapseln, etc. Sie verschlucken sich dabei und entwickeln mitunter ausgeprägte Aversionen gegen derartige Darreichungsformen. However, especially elderly patients often have difficulties in taking solid dosage forms such as tablets, capsules, etc. They choke them and sometimes develop pronounced aversion to such dosage forms.
- Um diesem Problem zu begegnen, wurden verschiedene Apparaturen entwickelt, mit deren Hilfe feste Darreichungsformen zerkleinert oder pulverisiert werden können ("tablet crusher"). To address this problem, various apparatuses have been developed can be crushed with the help of solid dosage forms or pulverized ( "tablet crusher"). Die Anwendung solcher Apparaturen erfolgt beispielsweise durch das Pflegepersonal in Altenheimen. The use of such equipment for example, by the nursing staff in nursing homes. Den pflegebedürftigen Personen werden dann die Darreichungsformen nicht als Tablette etc., sondern als Pulver verabreicht, beispielsweise um die Schwierigkeiten beim Herunterschlucken von Tabletten zu umgehen. The dependents, the dosage forms are then administered not as a tablet, etc., but as a powder, for example, to bypass the difficulties in swallowing tablets.
- Problematisch ist die Zerkleinerung der Darreichungsformen mit solchen Apparaturen jedoch, wenn es sich bei den Darreichungsformen um Retard-Formulierungen handelt. The problem with such equipment, the crushing of the dosage forms, however, if it is in the dosage forms are delayed-release formulations. Die Zerkleinerung führt nämlich im Regelfall dazu, dass die innere Struktur der Darreichungsform, welche für die retardierte Freisetzung verantwortlich ist, zerstört wird, wodurch die retardierende Wirkung aufgehoben wird. The comminution leads namely usually means that the internal structure of the dosage form, which is responsible for the sustained release, will be destroyed, whereby the retarding effect will be canceled. Infolge der Zerkleinerung werden die Diffusionswege der enthaltenen physiologisch wirksamen Substanzen verkürzt und/oder die Diffusionsbarrieren entfernt. As a result of comminution, the diffusion paths of the physiologically active substances contained therein are shortened and / or the diffusion barrier removed. So weist eine Retard-Formulierung, bei welcher die verzögerte Freisetzung mit Hilfe eines Filmüberzugs erreicht werden soll, nach der Zerkleinerung nur noch auf einem geringen prozentualen Anteil ihrer Feststoffoberfläche den Filmüberzug auf. Thus, a sustained-release formulation in which the delayed release by means of a film coating is to be achieved after reduction only on a small percentage of their solid surface the film coating on. Als Folge davon wird nach Verabreichung häufig die gesamte in der Darreichungsform ursprünglich enthaltene physiologisch wirksame Substanz in relativ kurzer Zeit freigesetzt, wodurch sprunghaft für eine relativ kurze Zeitspanne eine vergleichsweise sehr hohe Plasmakonzentration der Substanz erreicht wird. As a result, the total in the dosage form after administration often originally contained physiologically active substance in a relatively short time released, making leaps and bounds for a relatively short period of time a comparatively very high plasma concentration of the substance is achieved. Aus den ursprünglichen Retard-Formulierungen werden auf diese Weise "immediate release" Formulierungen. From the original slow-release formulations are thus "immediate release" formulations.
- Je nach physiologischer Wirksamkeit der Substanz kann dies jedoch erhebliche Nebenwirkungen hervorrufen, in Extremfällen sogar bis zum Tod des Patienten führen. However, depending on the physiological activity of the substance, this can cause serious side effects, leading in extreme cases even to the death of the patient. Beispiele für Substanzen mit einem solchen Gefährdungspotential sind Antiparkinsonmittel, Antiepileptika, Antidiabetika, Antihypertensiva, Antiarhythmika, etc. Examples of substances with such a hazard potential are antiparkinson agents, antiepileptic agents, antidiabetics, antihypertensives, antiarrhythmics, etc.
- Im Regelfall sind diese Gefahren den Personen, welche die Darreichungsformen für sich selbst oder für andere zerkleinern, nicht bewusst. As a rule, these are dangers to persons who crush the dosage forms for themselves or for others, not consciously. Es wurden Todesfälle von Patienten bekannt, welche wahrscheinlich auf eine Pulverisierung von Retard-Formulierungen durch Krankenschwestern bzw. Pfleger zurückzuführen sind. It became known deaths of patients who are likely due to pulverization of sustained-release formulations by nurses or carers. Hinsichtlich weiterer Einzelheiten kann beispielsweise auf JE Mitchell, Oral Dosage Forms That Should Not Be Crushed: 2000 Update. For further details, for example, on JE Mitchell, Oral Dosage Forms That Should Not Be Crushed: 2000 update. Hospital Pharmacy, 2000; Hospital Pharmacy, 2000; H. Miller et al., To Crush or Not to Crush, Nursing 2000; . H. Miller et al, To Crush or Not to Crush, Nursing 2000; R. Grittith et al., Tablet Crushing and the law: the implications for nursing; . R. Grittith et al, Tablet Crushing and the law: the implications for nursing; Prof. Nurse 2003; Prof. Nurse 2003; und JG Schier et al, Fatality from administration of labetalol and crushed extended-release nifedipine, Ann. and JG Schier et al Fatality from administration of labetalol and crushed extended-release nifedipine, Ann. Pharmacotherapy 2003 verwiesen werden. be referred Pharmacotherapy of 2003.
- Auch bei Kleinkindern können Retard-Formulierungen Probleme bereiten. Even in infants sustained-release formulations can cause problems. So können Kinder häufig feste Darreichungsformen nicht von Süßigkeiten unterscheiden. So children can not distinguish them from sweets often solid dosage forms. Finden die Kinder solche Darreichungsformen, beispielsweise weil ihre Eltern diese aus Unachtsamkeit in der Wohnung haben herumliegen lassen, so besteht die Gefahr, dass die Kinder die Darreichungsformen für Bonons halten, in den Mund nehmen und zerkauen. For the children of such dosage forms, for example, because their parents this carelessness in the home have released into the environment, there is a risk that the children keep the forms for sweets and put them in your mouth and chew. Handelt es sich dabei um Retard-Formulierungen, welche einen Arzneistoff in einer Dosierung enthalten, die für einen Erwachsenen bestimmt ist, so besteht in einem solchen Fall für das Kind bereits durch die größere enthaltene Arzneistoffmenge die Gefahr einer Überdosierung. Is this to sustained-release formulations containing a drug in a dosage that is intended for an adult, there is in such a case the child already contained the greater amount of drug the risk of overdose. Durch das Zerkauen der Darreichungsform und die damit einhergehende Aufhebung der Retard-Wirkung wird diese Gefahr jedoch noch verstärkt, da die bereits ohnehin zu hohe Dosis zusätzlich auch noch innerhalb eines stark verkürzten Zeitintervalls freigesetzt wird, was bereits für einen Erwachsenen erhebliche Gefahren mit sich bringen würde, für ein Kind jedoch umso drastischere Folgen haben kann. By chewing the dosage form and the consequent cancellation of the delayed action, this risk is, however, exacerbated because the already anyway too high a dose of the additional release also within a much shorter time interval, which would already make for an adult significant dangers , for a child but more can have drastic consequences.
- Das Kauen von Retard-Formulierungen kann auch bei Erwachsenen zu einer Überdosierung der enthaltenen Substanz führen. Chewing sustained-release formulations can lead to an overdose of the substance contained in adults. So zerkauen Erwachsene die Darreichungsformen mitunter ganz bewusst, da sie sich – oft in Unkenntnis der Art und des Zwecks einer Retard-Formulierung – davon einen schnelleren Wirkungserfolg versprechen. So chew adults, the dosage forms sometimes deliberately, as they are - often unaware of the nature and purpose of a sustained-release formulation - of which promise a quicker effect.
- Eine bekannte Möglichkeit zur Reduzierung der Gefahren, welche von einer Zerkleinerung der Retard-Formulierungen ausgehen, besteht darin, der Darreichungsform Antagonisten, dh Gegenmittel, oder Verbindungen, die zu physiologischen Abwehrreaktionen führen, zuzusetzen, wobei die physiologische Wirkung dieser Zusatzstoffe möglichst nur dann entfaltet wird, wenn die Darreichungsform vor der Verabreichung zerkleinert wurde. One known way to reduce the dangers posed by a comminution of the sustained-release formulations, is to provide the dosage form antagonists, ie, antidote, or compounds which cause a physiological defense reactions to add, wherein the physiological effect of these additives possible only unfolds when the dosage form was crushed prior to administration. Diese Methode hat jedoch den Nachteil, dass die physiologisch wirksame Substanz dennoch in nichtretardierter Form verabreicht wird und dass der Organismus zusätzlich mit einer weiteren physiologisch wirksamen Substanz, zB einem Gegenmittel belastet oder eine Abwehrreaktion, wie zB Erbrechen, ausgelöst wird. However, this method has the advantage that the physiologically active substance is administered in yet nichtretardierter shape and that the organism or additionally loaded with another physiologically active substance, such as an antidote a defense reaction, such as emesis, triggers the disadvantage.
- Es besteht daher ein Bedarf an pharmazeutischen Darreichungsformen mit retardierter Freisetzung, welche die Gefahr von Überdosierungen vermindern, so dass auf Gegenmittel etc. verzichtet werden kann. may be, there is a need for pharmaceutical dosage forms with delayed release, that reduce the risk of overdose, so that no antidote etc..
- Der Erfindung liegt somit die Aufgabe zugrunde, eine Darreichungsform bereitzustellen, welche eine physiologisch wirksame Substanz retardiert freisetzt, jedoch die Gefahr von Überdosierungen, insbesondere infolge einer unsachgemäßen Handhabung der Darreichungsform, wie Kauen, Mahlen, Mörsern, etc. vermindert. The invention is thus based on the object to provide a dosage form which releases a physiologically active substance retarded, however, reduces the risk of overdose, particularly as a result of improper handling of the dosage form, such as chewing, grinding in a mortar etc..
- Es wurde überraschend gefunden, dass diese Aufgabe gelöst wird durch eine Darreichungsform umfassend It has surprisingly been found that this object is achieved by a dosage form comprising
- – eine physiologisch wirksame Substanz (A) mit zumindest teilweise retardierter Freisetzung (= Komponente (A)); - a physiologically active substance (A) with at least partially retarded release (= component (A));
- – gegebenenfalls einen oder mehrere physiologisch verträgliche Hilfsstoffe (B) (= Komponente (B)); - optionally one or more physiologically acceptable auxiliary substances (B) (= component (B)); und and
- – ein synthetisches oder natürliches Polymer (C) (= Komponente (C)); - a synthetic or natural polymer (C) (= component (C));
- Die erfindungsgemäße Darreichungsform weist über einen weiten Temperaturbereich eine mechanische Festigkeit auf, neben der Bruchfestigkeit ggf. auch ausreichende Härte und Schlagzähigkeit, so dass sie durch Kauen, Mörsern, Hämmern, etc. und auch mit Hilfe kommerziell erhältlicher Apparaturen zur Pulverisierung herkömmlicher Darreichungsformen praktisch nicht zerkleinert oder pulverisiert werden kann. The dosage form according to the invention optionally comprises over a wide temperature range, mechanical strength, in addition to the breaking strength and sufficient hardness and impact strength, so they are not crushed practically by chewing, mortars, hammering, etc. and also commercially available with the aid of apparatus for pulverizing conventional dosage forms or can be pulverized. Dabei wird dies nicht notwendigerweise durch die Härte der Darreichungsform erreicht. Here, this is not necessarily achieved by the hardness of the dosage form. So kann insbesondere auch ihre Schlagzähigkeit dazu führen, dass sich die erfindungsgemäße Darreichungsform zwar infolge einer mechanischen Einwirkung von außen verformen lässt, beispielswiese mit Hilfe eines Hammers, dabei jedoch nicht in mehrere Bruchstücke zerfällt. Thus, in particular also perform their impact resistance to the fact that the dosage form of the invention can indeed deform due to a mechanical action from outside, for meadow using a hammer, however it does not disintegrate into multiple fragments. Eine Zerkleinerung gelingt selbst dann nicht, wenn die Darreichungsform zur Erhöhung ihrer Sprödigkeit zunächst abgekühlt wird, beispielsweise auf Temperaturen unterhalb von –25°C, –40°C oder etwa in flüssigem Stickstoff. A comminution is not possible even if the dosage form to increase its brittleness is first cooled, for example to temperatures below -25 ° C, -40 ° C or about in liquid nitrogen.
- Als Folge davon bleibt die retardierte Freisetzung erhalten und eine Überdosierung infolge unsachgemäßer Handhabung der Darreichungsform wird effektiv verhindert. As a result, the sustained release is maintained and an overdose due to improper handling of the dosage form is effectively prevented.
- Unter retardierter Freisetzung wird erfindungsgemäß bevorzugt ein Freisetzungsprofil verstanden, bei dem die physiologisch wirksame Substanz mit dem Ziel einer verlängerten therapeutischen Wirkung über einen längeren Zeitraum bei verringerter Einnahmefrequenz freigegeben wird. Under delayed release is understood according to the invention preferably has a release profile in which the physiologically active substance is released with the aim of a prolonged therapeutic action over a longer period at reduced frequency of intake. Insbesondere wird dies bei peroraler Verabreichung erreicht. This is achieved in particular when administered orally. Der Ausdruck "mit zumindest teilweise retardierter Freisetzung" umfasst erfindungsgemäß jegliche Darreichungsformen, welche eine modifizierte Freigabe der darin enthaltenen physiologisch wirksamen Substanzen gewährleisten. The expression "with at least partially retarded release" according to the invention comprises any dosage forms which provide a modified release of the physiologically active substances contained therein. Bei den Darreichungsformen handelt es sich bevorzugt um überzogene oder nicht überzogene Darreichungsformen, die mit speziellen Hilfsstoffen, nach besonderen Verfahren oder durch Kombination beider Möglichkeiten hergestellt werden, um die Freisetzungsgeschwindigkeit oder den Ort der Freisetzung gezielt zu verändern. The dosage forms are preferably coated or uncoated dosage forms which are produced using special excipients, according to particular methods or by a combination of both options to modify the release rate or location of release specifically. Hinsichtlich des zeitlichen Ablaufs der Freigabe sind bei den ertindungsgemäßen Darreichungsformen folgende Arten umfasst: verzögerte Freigabe (extended release, delayed release), gestaffelte Freigabe (repeat action release), hinhaltende Freigabe (prolonged release) und gleichmäßig hinhaltende Freigabe (sustained release). With regard to the timing of the release of the following types are included in the dosage forms ertindungsgemäßen: delayed release (extended release, delayed release), repeat action release (repeat action release), sustained release (prolonged release) and sustained release (sustained release). Hinsichtlich weiterer Einzelheiten kann beispielsweise verwiesen werden auf KH Bauer, Lehrbuch der Pharmazeutischen Technologie, 6. Auflage, WVG Stuttgart, 1999. For further details, for example, can be made to KH Bauer, Textbook of Pharmaceutical Technology, 6th edition, WVG Stuttgart., 1999
- In einer bevorzugten Ausführungsform setzt die erfindungsgemäße Darreichungsform unter physiologischen Bedingungen nach 5 Stunden höchstens 99%, bevorzugter höchstens 90%, bevorzugter höchstens 75%, noch bevorzugter höchstens 50%, am bevorzugtesten höchstens 40% und insbesondere höchstens 30% der Substanz (A) frei. In a preferred embodiment the dosage form according to the invention under physiological conditions after 5 hours of not more than 99%, more preferably at most 90%, more preferably at most 75%, more preferably at most 50%, bevorzugtesten at most 40% and in particular at most 30% of the substance (A) free , Dabei ist es besonders bevorzugt, dass die Darreichungsform in diesem Fall weder Tramadol Hydrochlorid, noch Oxycodon Hydrochlorid, bevorzugter kein Opioid [N02A] enthält (zur Bedeutung von "N02A" siehe unten). It is particularly preferred that the dosage form in this case, neither tramadol hydrochloride, nor oxycodone hydrochloride, more preferably no opioid [N02A] (for the meaning of "N02A" see below). Die Freisetzung wird dabei bevorzugt gemäß den standardisierten Verfahren im Europäischen Arzneibuch ermittelt, vorzugsweise unter den in Beispiel 1 angegebenen Bedingungen. The release is preferably determined according to the standardized method in the European Pharmacopoeia, preferably under the conditions given in Example 1 conditions.
- Durch den Einsatz bestimmter Polymere in geeigneter Menge und unter geeigneten Bedingungen wird erfindungsgemäß erreicht, dass die Darreichungsform eine Bruchfestigkeit von mindestens 400 N, vorzugsweise mindestens 500 N aufweist (gemessen, wie in der Beschreibung angegeben). Through the use of certain polymers in an appropriate quantity and under appropriate conditions that the dosage form exhibits a breaking strength of at least 400 N, preferably at least 500 N is achieved according to the invention, (measured as stated in the description). Dadurch gelingt es, eine Zerkleinerung, zB ein Pulverisieren der Darreichungsform mit üblichen Mitteln wirksam zu verhindern. This is to prevent a crushing, such as a pulverizing the dosage form by conventional means effectively manage.
- Unter einer Zerkleinerung wird erfindungsgemäß die Pulverisierung der Darreichungsform unter Krafteinwirkung mit üblichen Mitteln, wie z. Under a crusher according to the invention, the pulverization of the dosage form by application of force with conventional means, such. B. Mörser und Pistill, Hammer, Schlegel oder anderen gebräuchlichen Mitteln zum Pulverisieren, insbesondere auch eigens dafür entwickelten Vorrichtungen (tablet crusher) verstanden, wobei ein gegebenenfalls anfallender Feinanteil (Teilchengröße gleich oder kleiner 0,3 mm) von 5 Gew.-% nicht überschritten werden darf. B. mortar and pestle, hammer, mallet or other usual means for pulverisation, in particular specially designed devices (tablet crusher) understood, wherein an optionally incurred fine fraction (particle size less than 0.3 mm or equal to) of 5 wt .-% non- may be exceeded.
- Die erfindungsgemäße Darreichungsform ist daher zur Verhinderung der Überdosierung physiologisch wirksamer Substanzen geeignet, insbesondere von Nahrungsergänzungsmitteln und Arzneistoffen, welche in Retard-Formulierungen bereitgestellt werden. The dosage form according to the invention is therefore suitable for preventing overdose of physiologically active substances, in particular of food supplements and drugs, which are provided in sustained release formulations. Auf Gegenmittel, Reizstoffe, etc. kann dabei verzichtet werden. On antidotes, irritants, etc. can be dispensed with. Neben der Verhinderung von Überdosierungen und den damit einhergehenden Risiken für den Patienten gewährleisten die erfindungsgemäßen Darreichungsformen außerdem, dass die übrigen Vorteile der Retard-Formulierung, wie beispielsweise eine gleichmäßige Freigabe über einen längeren Zeitraum, erhalten bleiben und nicht ohne weiteres aufgehoben werden können. In addition to preventing overdoses and the associated risks to the patient dosage forms according to the invention also ensure that the other advantages of sustained-release formulation, such as a uniform release over a longer period, are preserved and can not be removed easily.
- Zur Erzielung der notwendigen Bruchfestigkeit der erfindungsgemäßen Darreichungsform wird mindestens ein synthetisches oder natürliches Polymer (C) eingesetzt, welches maßgeblich zur erhöhten Bruchfestigkeit der Darreichungsform beiträgt. To achieve the necessary breaking strength of the dosage form according to the invention at least one synthetic or natural polymer (C) is used, which contributes significantly to the increased breaking strength of the dosage form. Die Bruchfestigkeit der Darreichungsform beträgt mindestens 400 N, wobei die Bruchfestigkeit nach der in der Beschreibung angegebenen Methode bestimmt wird. The breaking strength of the dosage form is at least 400 N, the breaking strength is determined according to the method given in the description. In einer bevorzugten Ausführungsform beträgt die Bruchfestigkeit der Darreichungsform mindestens 500 N, bevorzugter mindestens 600 N, bevorzugter mindestens 700 N, noch bevorzugter mindestens 800 N, noch bevorzugter mindestens 900 N, am bevorzugtesten mindestens 1000 N und insbesondere mindestens 1100 N. In a preferred embodiment, the breaking strength of the dosage form is at least 500 N, preferably at least 600 N, preferably at least 700 N, more preferably at least 800 N, more preferably at least 900 N, at least 1000 N bevorzugtesten and in particular at least 1100 N.
- Bevorzugt enthält die erfindungsgemäße Darreichungsform mindestens ein Polymer (C) ausgewählt aus der Gruppe bestehend aus Polyalkylenoxid, vorzugsweise Polymethylenoxid, Polyethylenoxid, Polypropylenoxid; Preferably, the dosage form of the invention contains at least one polymer (C) is selected from the group consisting of polyalkylene oxide, preferably polymethylene oxide, polyethylene oxide, polypropylene oxide; Polyethylen, Polypropylen, Polyvinylchlorid, Polycarbonat, Polystyrol, Polyacrylat, Poly(hydroxyfettsäuren), wie z. Polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, poly (hydroxyfatty acids), such as. B. Poly(3-hydroxybutyrat-co-3-hydroxyvalerat) (Biopol ® ), Poly(hydroxyvaleriansäure), Polycaprolacton, Polyvinylalkohol, Polyesteramid, Polyethylensuccinat, Polylacton, Polyglykolid, Polyurethan, Polyvinylpynolidon, Polyamid, Polylactid, Polyacetal (zB Polysaccharide ggf. mit modifizierten Seitenketten), Polylactidglykolid, Polylacton, Polyglykolid, Polyorthoester, Polyanhydrid, Blockpolymer aus Polyethylenglykol und Polybutylenterephthalat (Polyactive ® ), Polyanhydrid (Polifeprosan), deren Copolymerisaten, und Mischungen aus mindestens zwei der genannten Polymere. B. Poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol ®), poly (hydroxyvaleric acid), polycaprolactone, polyvinyl alcohol, polyesteramide, polyethylene succinate, polylactone, polyglycolide, polyurethane, polyvinylpyrrolidone, polyamide, polylactide, polyacetal (eg polysaccharides optionally (with modified side chains), Polylactidglykolid, polylactone, polyglycolide, polyorthoester, polyanhydride, block polymer of polyethylene glycol and polybutylene terephthalate (Polyactive ®), polyanhydride polifeprosan), copolymers thereof, and mixtures of at least two of said polymers.
- Bevorzugt sind hochmolekulare, thermoplastische Polyalkylenoxide. high molecular weight thermoplastic polyalkylene oxides are preferred. Besonders bevorzugt sind hochmolekulare Polyethylenoxide mit einem, vorzugsweise gewichtsmittleren Molekulargewicht (M w ) oder viskositätsmittleren Molekulargewicht (M η ) von mindestens 0,5 10 6 g/mol, bevorzugt mindestens 1,0 10 6 g/mol, bevorzugter mindestens 2,5 10 6 g/mol, noch bevorzugter mindestens 5,0 10 6 g/mol, am bevorzugtesten mindestens 7,5 10 5 g/mol und insbesondere mindestens 10 10 6 g/mol, bevorzugt 1,0 bis 15 10 6 g/mol. Particularly preferred are high molecular weight polyethylene oxides with a preferably weight average molecular weight (Mw) or viscosity average molecular weight (M η) of at least 0.5 10 6 g / mol, preferably at least 1.0 10 6 g / mol, more preferably at least 2.5 10 6 g / mol, more preferably at least 5.0 x 10 6 g / mol, bevorzugtesten at least 7.5 10 5 g / mol and in particular at least 10 10 6 g / mol, preferably from 1.0 to 15 10 6 g / mol. Dem Fachmann sind geeignete Methoden bekannt, wie M w bzw. M η bestimmt werden können. The skilled worker is aware of suitable methods, such as M w and M η can be determined. Vorzugsweise erfolgt die Bestimmung von M η durch Theologische Messungen und die Bestimmung von M w durch Gelpermeationschromatographie (GPC) an geeigneten Phasen. Preferably, the determination of M η by rheological measurements and the determination of Mw by gel permeation chromatography (GPC) at appropriate phases.
- Die Polymere (C) weisen bei 25 °C bevorzugt eine Viskosität von 4.500 bis 17.600 cP, gemessen in einer 5 Gew.-% wässrigen Lösung mit Hilfe eines Brookfield Viskosimeters, Model RVF (Spindel Nr. 2/Rotationsgeschwindigkeit 2 rpm), von 400 bis 4.000 cP, gemessen an einer 2 Gew.-% wässrigen Lösung mit Hilfe des genannten Viskosimeters (Spindel Nr. 1 bzw. 3/Rotationsgeschwindigkeit 10 rpm) bzw. von 1.650 bis 10.000 cP, gemessen an einer 1 Gew.-% wässrigen Lösung mit Hilfe des genannten Viskosimeters (Spindel Nr. 2/Rotationsgeschwindigkeit 2 rpm) auf. The polymers (C) have at 25 ° C preferably has a viscosity from 4,500 to 17,600 cP, measured in a 5 wt .-% aqueous solution using a Brookfield viscometer, Model RVF (spindle no. 2 / rotational speed 2 rpm), of 400 to 4000 cP, measured on a 2 wt .-% aqueous solution using the stated viscosimeter (spindle no. 1 or 3 / rotational speed 10 rpm) or 1,650 to 10,000 cP, measured on a 1 wt .-% aqueous solution using the stated viscosimeter (spindle no. 2 / rotational speed 2 rpm).
- Das Polymer (C) wird bevorzugt als Pulver eingesetzt. The polymer (C) is preferably used as a powder. Es kann in Wasser löslich sein. It may be soluble in water.
- Vorzugsweise wird das Polymer (C) in einer Menge von mindestens 20 Gew.-%, bevorzugter mindestens 30 Gew.-%, noch bevorzugter mindestens 40 Gew.-%, am bevorzugtesten mindestens 50 Gew.-% und insbesondere mindestens 60 Gew.-%, bezogen auf das Gesamtgewicht der Darreichungsform, eingesetzt. Preferably, the polymer (C) in an amount of at least 20 wt .-%, more preferably at least 30 wt .-%, more preferably at least 40 wt .-%, at least 50 wt .- bevorzugtesten% and in particular at least 60 weight %, based on the total weight of the dosage form.
- Die erfindungsgemäße Darreichungsform eignet sich für die Verabreichung von mehreren physiologisch wirksamen Substanzen (A) in einer Darreichungsform. The dosage form according to the invention is suitable for the administration of more physiologically active substances (A) in a dosage form. Vorzugsweise erhält die Darreichungsform nur eine bestimmte physiologisch wirksame Substanz (A), bevorzugt ein Nahrungsergänzungsmittel oder einen Arzneistoff (= pharmazeutischen Wirkstoff). Preferably, the dosage form is obtained only a certain physiologically active substance (A), preferably a food supplement or a drug (= active pharmaceutical ingredient).
- In einer bevorzugten Ausführungsform der erfindungsgemäßen Darreichungsform enthält sie keine psychotrop wirkende Substanz. In a preferred embodiment, the inventive dosage form contains no psychotropic active substances. Dem Fachmann ist bekannt, welche Substanzen eine psychotrope Wirkung haben. The skilled worker knows which substances have a psychotropic effect. Gemeinhin haben Substanzen, welche psychische Prozesse beeinflussen, eine psychotrope Wirkung, dh eine spezifische Wirkung auf psychische Funktionen. have commonly substances that influence mental processes, a psychotropic effect, ie a specific effect on mental functions. Substanzen mit psychotroper Wirkung können somit die Stimmung beeinflussen, entweder aufhellend oder dämpfend. Substances with a psychotropic action may thus influence mood, either raising or lowering it. Zum Zwecke der Beschreibung zählen insbesondere Opioide, Stimulanzien, Tranquilizer (Barbiturate und Benzodiazepine) und weitere Betäubungsmittel zu den Substanzen mit psychotroper Wirkung. For purposes of description include in particular opioids, stimulants, tranquilizers (barbiturates and benzodiazepines) and other narcotics substances with a psychotropic action. Bevorzugt handelt es sich bei Substanzen mit psychotroper Wirkung um Substanzen, die insbesondere bei nicht bestimmungsgemäßer Art der Verabreichung (insbesondere in der Absicht eines Missbrauchs) ein gegenüber der bestimmungsgemäßen oralen Applikation beschleunigtes Anfluten des Wirkstoffes mit dem von einem Missbraucher gewünschten Ergebnis bewirken, nämlich den Kick. It is preferable that effect (in particular with the intention of abuse) one with respect to the intended oral administration accelerated rise in level of the active ingredient with the desired of an abuser result for substances with a psychotropic action substances which especially at non-intended route of administration, namely, the kick , Dieser Kick kann zB erreicht werden, wenn die gepulverte Darreichungsform nasal appliziert, dh geschnupft wird. This kick can be achieved, for example, if the powdered dosage form is administered nasally, ie is sniffed. Bevorzugt sind Substanzen mit psychotroper Wirkung solche Substanzen, welche (bei entsprechender Dosierung, Darreichungsform und Darreichungsart) die menschliche Verstandestätigkeit und/oder Sinneswahrnehmung in einer Weise beeinflussen, dass sie grundsätzlich zu einem Missbrauch geeignet sind. Preferred are substances with a psychotropic action such substances which human intellect and / or sensory perception influenced (with appropriate dosage, dosage form and Darreichungsart) in such a way that they are in principle suited to abuse.
- Die folgenden Opioide, Tranquillanzien oder anderen Betäubungsmittel sind Substanzen mit psychotroper Wirkung und sind daher erfindungemäß bevorzugt nicht in der Darreichungsform enthalten: Alfentanil, Allobarbital, Allylprodin, Alphaprodin, Alprazolam, Amfepramon, Amfetamin, Amfetaminil, Amobarbital, Anileridin, Apocodein, Barbital, Bemidon, Benzylmorphin, Bezitramid, Bromazepam, Brotizolam, Buprenorphin, Butobarbital, Butorphanol, Camazepam, Carfentanil, Cathin/D-Norpseudoephedrin, Chlordiazepoxid, Clobazam, Clofedanol, Clonazepam, Clonitazen, Clorazepat, Clotiazepam, Cloxazolam, Cocain, Codein, Cyclobarbital, Cyclorphan, Cyprenorphin, Delorazepam, Desomorphin, Dextromoramid, Dextropropoxyphen, Dezocin, Diampromid, Diamorphon, Diazepam, Dihydrocodein, Dihydromorphin, Dihydromorphon, Dimenoxadol, Dimephetamol, Dimethylthiambuten, Dioxaphetylbutyrat, Dipipanon, Dronabinol, Eptazocin, Estazolam, Ethoheptazin, Ethylmethylthiambuten, Ethylloflazepat, Ethylmorphin, Etonitazen, Etorphin, The following opioids, tranquilizers or other drugs are substances with a psychotropic action and are therefore erfindungemäß not preferred in the dosage form include: alfentanil, Allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone, amphetamine, Amfetaminil, amobarbital, anileridine, apocodeine, barbital, Bemidon, benzylmorphine, bezitramide, bromazepam, brotizolam, buprenorphine, Butobarbital, butorphanol, camazepam, carfentanil, cathine / D-norpseudoephedrine, chlordiazepoxide, clobazam, Clofedanol, clonazepam, clonitazene, clorazepate, clotiazepam, cloxazolam, cocaine, codeine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, diazepam, dihydrocodeine, dihydromorphine, dihydromorphone, dimenoxadol, Dimephetamol, dimethylthiambutene, dioxaphetyl, dipipanone, dronabinol, eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethyl loflazepate, ethylmorphine, etonitazene, etorphine, Fencamfamin, Fenetyllin, Fenpipramid, Fenproporex, Fentanyl, Fludiazepam, Flunitrazepam, Flurazepam, Halazepam, Haloxazolam, Heroin, Hydrocodon, Hydromorphon, Hydroxypethidin, Isomethadon, Hydroxymethylmorphinan, Ketazolam, Ketobemidon, Levacetylmethadol (LAAM), Levomethadon, Levorphanol, Levophenacylmorphan, Levoxemacin, Lofentanil, Loprazolam, Lorazepam, Lormetazepam, Mazindol, Medazepam, Mefenorex, Meperidin, Meprobamat, Metapon, Meptazinol, Metazocin, Methylmorphin, Metamfetamin, Methadon, Methaqualon, 3-Methylfentanyl, 4-Methylfentanyl, Methylphenidat, Methylphenobarbital, Methyprylon, Metopon, Midazolam, Modafinil, Morphin, Myrophin, Nabilon, Nalbuphen, Nalorphin, Narcein, Nicomorphin, Nimetazepam, Nitrazepam, Nordazepam, Norlevorphanol, Normethadon, Normorphin, Norpipanon, Opium, Oxazepam, Oxazolam, Oxycodon, Oxymorphon, Papaver somniferum, Papaveretum, Pemolin, Pentazocin, Pentobarbital, Pethidin, Phenadoxon, Phenomorphan, Phenazocin, Phenoperidin, Piminodin, Pholcodein, Phenm Fencamfamin, fenetylline, Fenpipramid, fenproporex, fentanyl, fludiazepam, flunitrazepam, flurazepam, halazepam, Haloxazolam, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Hydroxymethylmorphinan, ketazolam, ketobemidone, levacetylmethadol (LAAM), levomethadone, levorphanol, levophenacylmorphan, Levoxemacin, lofentanil , loprazolam, lorazepam, lormetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate, Metapon, meptazinol, metazocine, methyl morphine, metamfetamine, methadone, methaqualone, 3-methylfentanyl, 4-methylfentanyl, methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil , morphine, myrophine, nabilone, Nalbuphen, nalorphine, narceine, nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxazepam, oxazolam, oxycodone, oxymorphone, Papaver somniferum, papaveretum, pemoline, pentazocine, pentobarbital, pethidine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, pholcodeine, Phenm etrazin, Phenobarbital, Phentermin, Pinazepam, Pipradrol, Piritramid, Prazepam, Profadol, Proheptazin, Promedol, Properidin, Propoxyphen, Remifentanil, Secbutabarbital, Secobarbital, Sufentanil, Temazepam, Tetrazepam, Tilidin (cis und trans)), Tramadol, Triazolam, Vinylbital, N-(1-Methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamid, (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R, 2R, 4S)-2-[Dimethylamino)methyl-4-(p-fluorbenzyloxy)-1-(m-methoxyphenyl)cyclohexanol, (1R, 2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol, (1S, 2S)-3(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (2R, 3R)-1-Dimethylamino-3(3-Methoxy-phenyl)-2-methyl-pentan-3-ol, (1RS, 3RS, 6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexan-1,3-diol, vorzugsweise als Racemat, 3-(2-Dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl 2-(4-isobutyl-phenyl)-propionat, 3-(2-Dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(6-methoxy-naphthalen-2-yl)-xpropionat, 3-(2-Dimethylaminomethyl-cyclohex-1-enyl)-phen etrazin, phenobarbital, phentermine, pinazepam, Pipradrol, piritramide, Prazepam, profadol, proheptazine, promedol, properidine, propoxyphene, remifentanil, BUTABARBITAL, secobarbital, sufentanil, temazepam, tetrazepam, tilidine (cis and trans)), tramadol, triazolam, vinylbital, N- (1-methyl-2-piperidinoethyl) -N- (2-pyridyl) propionamide, (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (1R, 2R, 4S) -2- [dimethylamino) methyl-4- (p-fluorobenzyloxy) -1- (m-methoxyphenyl) cyclohexanol, (1R, 2R) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol, (1S, 2S) -3 (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (2R, 3R) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, preferably as racemate, 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl 2- (4-isobutyl-phenyl) -propionate, 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl 2- (6-methoxy-naphthalen-2-yl) -xpropionat, 3- (2-dimethylaminomethyl-cyclohex -phen -1-enyl) yl 2-(4-isobutyl-phenyl)-propionat, 3-(2-Dimethylaminomethyl-cyclohex-1-enyl)- phenyl 2-(6-methoxy-naphthalen-2-yl)-propionat, (RR-SS)-2-Acetoxy-4-trifluoromethyl-benzoesäure 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-Hydroxy-4-trifluoromethyl-benzoesäure 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-4-Chloro-2-hydroxy-benzoesäure 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-Hydroxy-4-methyl-benzoesäure 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-Hydroxy-4-methoxy-benzoesäure 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl-ester, (RR-SS)-2-Hydroxy-5-nitro-benzoesäure 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2',4'-Difluoro-3-hydroxy-biphenyl-4-carbonsäure 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester sowie entsprechende stereoisomere Verbindungen, jeweils deren entsprechende Derivate, physiologisch verträglichen Enantiomere, Ster yl 2- (4-isobutyl-phenyl) -propionate, 3- (2-dimethylaminomethyl-cyclohex-1-enyl) - phenyl 2- (6-methoxy-naphthalen-2-yl) propionate, (RR-SS) - 2-acetoxy-4-trifluoromethyl-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy-4-trifluoromethyl-benzoic acid 3- (2-dimethylaminomethyl-1- hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -4-chloro-2-hydroxy-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy- 4-methyl-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy-4-methoxy-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) phenyl ester, (RR-SS) -2-hydroxy-5-nitro-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2 ', 4'-difluoro -3-hydroxy-biphenyl-4-carboxylic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester and corresponding stereoisomeric compounds, in each case corresponding derivatives thereof, physiologically acceptable enantiomers, Ster eoisomere, Diastereomere und Racemate und deren physiologisch verträglichen Derivate, vorzugsweise Ether, Ester oder Amide, und jeweils deren physiologisch verträgliche Verbindungen, insbesondere deren Salze und Solvate, besonders bevorzugt Hydrochloride. eoisomere, diastereomers and racemates and the physiologically acceptable derivatives thereof, preferably ethers, esters or amides, and in each case the physiologically acceptable compounds, in particular salts and solvates thereof, particularly preferably hydrochlorides.
- Insbesondere bevorzugt enthält die erfindungsgemäße Darreichungsform keine Substanz ausgewählt aus der Gruppe bestehend aus Opioiden [A07DA, N01AH, N02A, R05DA, R05FA,], Barbituraten [N01AF, N01AG, N03AA], Benzodiazepin-Derivaten [N03AE], Mitteln zur Behandlung der Opiatabhängigkeit [N07BC], Anxiolytika [N05B], Hypnotika und Sedativa [N05C], Psychostimulanzien, Mitteln zur Behandlung von Aufmerksamkeitsdefizit/Hyperaktivitätsstörung (ADHD) und Nootropika [N06B], Antiemetika [A04A], Abmagerungsmitteln ausgenommen Diätetika [A08A], zentral wirkenden Muskelrelaxantien [M03B], und Antidoten [V03AB]. Particularly preferably, the inventive dosage form contains no substance selected from the group consisting of opioids [A07DA, N01AH, N02A, R05DA, R05FA,], barbiturates [N01AF, N01AG, N03AA] benzodiazepine derivatives [N03AE], agents for the treatment of opiate addiction [ N07BC], anxiolytics [N05B], hypnotics and sedatives [N05C], psychostimulants, agents for the treatment of attention deficit / hyperactivity disorder (ADHD) and nootropics [N06B], antiemetics [A04A]; antiobesity excluding diet [A08A], centrally acting muscle relaxants [M03B ], and antidotes [V03AB]. Die in eckigen Klammem angegebenen Bezeichnungen entsprechen dabei dem ATC-Index, wie er von der WHO zur Klassifizierung der Arzneistoffe verwendet wird (bevorzugter Stand: Januar 2005). The names given in square brackets correspond to as used by the WHO for the classification of drugs to the ATC index (preferably, as of January 2005). Hinsichtlich weiterer Einzelheiten zum ATC-Index kann beispielsweise verwiesen werden auf U. Fricke, J. Günther, Anatomischtherapeutisch-chemische Klassifikation mit Tagesdosen für den deutschen Arzneimittelmarkt: Methodik der ATC-Klassifikation und DDD-Festlegung. For further details on the ATC Index, for example, be made to U. Fricke, J. Gunther, Anatomical Therapeutic Chemical Classification with daily doses for the German pharmaceutical market: methodology of the ATC classification and DDD down. ATC-Index mit DDD-Angaben, Wissenschaftliches Institut der AOK; ATC Index with DDD information, Scientific Institute of the AOK; und Swiss Pharmaceutical Society, Index Nominum: International Drug Directory, CRC Press; and Swiss Pharmaceutical Society, Index Nominum: International Drug Directory, CRC Press; 18th edition (January 31, 2004). 18th edition (January 31, 2004).
- In einer bevorzugten Ausführungsform enthält die erfindungsgemäße Darreichungsform keine den Nasen- und/oder Rachenraum reizenden Stoffe, dh Stoffe, die bei Applikation über den Nasen- und/oder Rachenraum eine Reaktion des Körpers hervorrufen, welche entweder für den Patienten so unangenehm ist, dass er die Applikation nicht weiter fortsetzen will oder kann, so zB ein Brennen, oder auf physiologische Art und Weise einer Aufnahme des entsprechenden Wirkstoffes entgegenwirken, zB über eine vermehrte nasale Sekretbildung oder Niesen. In a preferred embodiment the dosage form according to the invention does not contain the nasal passages and / or pharynx substances, ie substances which cause when applied via the nasal passages and / or pharynx a physical reaction which is either so unpleasant for the patient that he will not continue administration, or may, for example burning, or physiologically counteracts manner taking of the corresponding active ingredient, for example due to increased nasal secretion or sneezing. Weitere Beispiele für den Nasen- und/oder Rachenraum reizende Stoffe sind solche Stoffe, die ein Brennen, einen Juckreiz, einen Niesreiz, eine vermehrte Sekretbildung oder eine Kombination mindestens zweier dieser Reize verursachen. Further examples of the nasal passages and / or pharynx which substances are those substances which cause burning, itching, an urge to sneeze, increased formation of secretions or a combination of at least two of these stimuli. Entsprechende Stoffe und deren üblicherweise einzusetzenden Mengen sind dem Fachmann bekannt. Appropriate substances and the amounts to be used are commonly known in the art. So basieren einige der den Nasen- und/oder Rachenraum reizenden Stoffe auf einem oder mehreren Inhaltsstoffen oder einem oder mehreren Pflanzenteilen einer Schartstoffdroge. So some of the nasal passages and / or pharynx substances based on one or more constituents or one or more plant parts of a Schartmann substance drug. Entsprechende Scharfstoffdrogen sind dem Fachmann an sich bekannt und werden beispielsweise in "Pharmazeutische Biologie – Drogen und ihre Inhaltsstoffe" von Prof. Dr. Corresponding hot substance drugs are known to those skilled in the art and, for example, in "Pharmaceutical Biology - drugs and their ingredients" by Prof. Dr. Hildebert Wagner, 2., bearbeitete Auflage, Gustav Fischer Verlag, Stuttgart-New York, 1982, Seiten 82 ff., beschrieben. described Hildebert Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq.,. Die entsprechende Beschreibung wird hiermit als Referenz eingeführt und gilt als Teil der Offenbarung. The corresponding description is hereby introduced as a reference and is deemed part of the disclosure.
- Ferner enthält die erfindungsgemäße Darreichungsform bevorzugt keine Antagonisten für die physiologisch wirksame Substanz (A), vorzugsweise keine Antagonisten gegen psychotrope Substanzen, insbesondere keine Antagonisten gegen Opioide. Further, the dosage form according to the invention preferably contains no antagonists for the physiologically active substance (A), preferably no antagonists against psychotropic substances, in particular no antagonists of opioids. Für eine gegebene physiologisch wirksame Substanz (A) geeignete Antagonisten sind dem Fachmann bekannt und können als solche oder in Form entsprechender Derivate, insbesondere Ester oder Ether, oder jeweils in Form entsprechender physiologisch verträglicher Verbindungen, insbesondere in Form ihrer Salze oder Solvate vorliegen. For a given physiologically active substance (A) suitable antagonists are known in the art and can be used as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of their salts or solvates. Bevorzugt enthält die erfindungsgemäße Darreichungsform keine Antagonisten ausgewählt aus der Gruppe umfassend Naloxon, Naltrexon, Nalmefen, Nalid, Nalmexon, Nalorphin oder Naluphin, jeweils ggf. in Form einer entsprechenden physiologisch verträglichen Verbindung, insbesondere in Form einer Base, eines Salzes oder Solvates; Preferably, the inventive dosage form contains no antagonists selected from the group comprising naloxone, naltrexone, nalmefene, nalide, nalmexone, nalorphine or naluphine, in each case optionally in the form of a corresponding physiologically acceptable compound, in particular in the form of a base, a salt or solvate; und kein Neuroleptikum, zB eine Verbindung ausgewählt aus der Gruppe umfassend Haloperidol, Promethacin, Fluophenozin, Perphenazin, Levomepromazin, Thioridazin, Perazin, Chlorpromazin, Chlorprotheaxin, Zucklopantexol, Flupentexol, Prithipendyl, Zotepin, Penperidol, Pipanneron, Melperol und Bromperidol. and no neuroleptic, for example a compound selected from the group comprising haloperidol, promethazine, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, Chlorprotheaxin, Zucklopantexol, Flupentexol, Prithipendyl, zotepine, Penperidol, Pipanneron, Melperol and bromperidol.
- Darüber hinaus enthält die erfindungsgemäße Darreichungsform bevorzugt kein Emetikum. In addition, the dosage form preferably contains no emetic. Emetika sind dem Fachmann bekannt und können als solche oder in Form entsprechender Derivate, insbesondere Ester oder Ether, oder jeweils in Form entsprechender physiologisch verträglicher Verbindungen, insbesondere in Form ihrer Salze oder Solvate vorliegen. Emetics are known in the art and may be present as such or in the form of corresponding derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of their salts or solvates. Bevorzugt enthält die erfindungsgemäße Darreichungsform kein Emetikum auf Basis eines oder mehrerer Inhaltsstoffe von Radix Ipecacuanhae (Brechwurzel), zB auf Basis des Inhaltsstoffes Emetin, wie sie zB in „Pharmazeutische Biologie – Drogen und ihre Inhaltsstoffe" von Prof. Dr. Hildebert Wagner, 2., bearbeitete Auflage, Gustav Fischer Verlag, Stuttgart, New York 1982 beschrieben werden. Die entsprechende Literaturbeschreibung wird hiermit als Referenz eingeführt und gilt als Teil der Offenbarung. Bevorzugt enthält die erfindungsgemäße Darreichungsform auch kein Apomorphin als Emetikum. Preferably, the inventive dosage form contains no emetic based on one or more constituents of ipecacuanha (ipecac) root, for example based on the constituent emetine, as described for example in "Pharmazeutische Biologie - drugs and their ingredients" by Prof. Dr. Hildebert Wagner; 2. , revised edition, Gustav Fischer Verlag, Stuttgart, New York, 1982.. the corresponding literature description is hereby incorporated by reference and forms part of the disclosure. Preferably, the dosage form contains no apomorphine as an emetic.
- Schließlich enthält die erfindungsgemäße Darreichungsform bevorzugt auch keinen Bitterstoff. Finally, the dosage form of the invention preferably also contains no bitter substance. Bitterstoffe sowie die für den Einsatz wirksamen Mengen sind der US-2003/0064099 A1 zu entnehmen, deren entsprechende Offenbarung als Offenbarung der vorliegenden Anmeldung gelten soll und hiermit als Referenz eingeführt wird. Bitters and effective for use as the US-2003/0064099 A1 can be found in whose corresponding disclosure should be deemed as disclosure of the present application and is hereby incorporated by reference. Beispiele für Bitterstoffe sind Aromaöle, wie Pfefferminzöl, Eukalyptusöl, Bittermandelöl, Menthol, Fruchtaromastoffe, Aromastoffe von Zitronen, Orangen, Limonen, Grapefruit oder Mischungen davon, und/oder Denatonium-Benzoat. Examples of bitter substances are aromatic oils such as peppermint oil, eucalyptus oil, bitter almond oil, menthol, fruit flavors, flavors of lemons, oranges, limes, grapefruit or mixtures thereof, and / or denatonium benzoate.
- Somit enthält die erfindungsgemäße Darreichungsform bevorzugt weder Substanzen mit psychotroper Wirkung, noch den Nasen- und/oder Rachenraum reizende Stoffe, noch Antagonisten für die physiologisch wirksame Substanz (A), noch Emetika, noch Bitterstoffe. Thus, preferably the dosage form does not contain any substances with a psychotropic action, nor the nose and / or throat irritants, nor antagonists for the physiologically active substance (A), nor emetics, nor bitter substances.
- In einer bevorzugten Ausführungsform enthält die erfindungsgemäße Darreichungsform als physiologisch wirksame Substanz (A) ein Nahrungsergänzungsmittel. In a preferred embodiment, the dosage form of the invention contains as a physiologically active substance (A) is a dietary supplement. Nahrungsergänzungsmittel enthalten bevorzugt einen oder mehrere Nährstoffe in konzentrierter, dosierter, lebensmittel-untypischer Form. Dietary supplements preferably contain one or more nutrients in concentrated, dose atypical of foodstuffs form.
- Sie sollen die tägliche Nahrung in den Fällen ergänzen, in denen eine Versorgung durch die Nahrung unzureichend ist bzw. eine Ergänzung gewünscht wird. They are intended to supplement the daily food in those cases in which a supply of food is inadequate or supplementation is desired. Bevorzugt ist das Nahrungsergänzungsmittel ausgewählt aus der Gruppe bestehend aus Vitaminen, Mineralstoffen, Spurenelementen, Enzymen, Fettsäuren, Aminosäuren, und Antioxidantien. Preferably, the dietary supplement is selected from the group consisting of vitamins, minerals, trace elements, enzymes, fatty acids, amino acids, and antioxidants. Besonders bevorzugte Nahrungsergänzungsmittel sind Vitamine, Provitamine und deren Derivate, insbesondere Retinol, Calcitriol, Tocopherol, Phyllochinon, Thiamin, Riboflavin, Folsäure, Niacin (insbesondere Nicotinamid), Pantothensäure, Pyridoxal, Cobalamin, L-Ascorbinsäure, Biocytin, Biotin, und Karotinoide. Particularly preferred supplements are vitamins, provitamins and derivatives thereof, in particular retinol, Calcitriol, tocopherol, phylloquinone, thiamine, riboflavin, folic acid, niacin (in particular nicotinamide), pantothenic acid, pyridoxal, cobalamin, L-ascorbic acid, biocytin, biotin, and carotenoids.
- In einer bevorzugten Ausführungsform enthält die erfindungsgemäße Darreichungsform als physiologisch wirksame Substanz (A) einen Arzneistoff (= pharmazeutischen Wirkstoff), der eine Anwendung der Darreichungsform als Arzneimittel begründet und Ursache für deren Wirksamkeit ist. In a preferred embodiment, the dosage form of the invention contains as a physiologically active substance (A) is a drug (= active pharmaceutical ingredient) which confers application of the dosage form as a drug and cause for their effectiveness. Als Arzneistoffe kommen in der erfindungsgemäßen Darreichungsform grundsätzlich alle bekannten Arzneistoffe infrage, wobei die Arzneistoffe als solche, in Form ihrer Derivate, insbesondere Ester oder Ether, oder jeweils in Form entsprechender physiologisch verträglicher Verbindungen, insbesondere in Form ihrer entsprechenden Salze oder Solvate, als Racemate oder in angereicherter Form eines oder mehrerer Stereoisomere in der erfindungsgemäßen Darreichungsform vorliegen können. As drugs all known drugs used in the inventive dosage form principle in question, wherein the drugs as such, in the form of their derivatives, in particular esters or ethers, or in each case in the form of corresponding physiologically acceptable compounds, in particular in the form of their corresponding salts or solvates thereof, as racemates or may be one or more stereoisomers in the inventive dosage form in enriched form.
- Besonders bevorzugt enthält die erfindungsgemäße Darreichungsform eine Substanz (A) oder mehrere Substanzen (A) ausgewählt aus der Gruppe bestehend aus Particularly preferably, the inventive dosage form contains a substance (A) or more substances (A) selected from the group consisting of
- – Mitteln zur Behandlung und Vorbeugung von Erkrankungen des alimentären Systems und Stoffwechsels [A]; - agents for the treatment and prevention of diseases of the alimentary system and metabolism [A]; insbesondere Stomatologika [A01], Mitteln zur Behandlung und Vorbeugung von säurebedingten Erkrankungen [A02], Mitteln zur Behandlung und Vorbeugung von funktionellen gastrointestinalen Störungen [A03], Serotonin-5HT 3 -Antagonisten [A04AA], Antihistaminika [A04AB], Mitteln zur Gallen- und Lebertherapie [A05], Laxanzien [A06], Intestinalen Antiinfektiva [A07A], Intestinalen Adsorbentien [A07B], Elektrolyten mit Kohlenhydraten [A07C], Intestinalen Antiphlogistika [A07E], Mikrobiellen Antidiarrhoika [A07F], Digestiva einschließlich Enzymen [A09], Antidiabetika [A10], Vitaminen [A11], Mineralstoffen [A12], Anabolika zur systemischen Anwendung [A14] und Appetit stimulierenden Mitteln [A15]; in particular in stomatology [A01], agents for the treatment and prevention of acid-related disorders [A02], agents for the treatment and prevention of functional gastrointestinal disorders [A03], serotonin 5HT 3 antagonists [A04AA], antihistamines preparations [A04AB], means for bile and liver therapy [A05], laxatives [A06], Intestinal anti-infectives [A07A] Intestinal adsorbents [A07B], electrolytes with carbohydrates [A07C] Intestinal anti-inflammatory drugs [A07E] microbial antidiarrheals [A07F] Digestiva including enzymes [A09], antidiabetics [A10], vitamins [A11], minerals [A12], anabolic agents for systemic use [A14] and appetite stimulating agents [A15];
- – Mitteln zur Behandlung und Vorbeugung von Erkrankungen des Bluts und der blutbildenden Organe [B]; - agents for the treatment and prevention of diseases of the blood and blood-forming organs [B]; insbesondere antithrombotischen Mitteln [B01], Antihämorrhagika [B02], Antianämika [B03] und anderen Hämatologika [B06]; particularly antithrombotic agents [B01], antihemorrhagics [B02], antianaemic [B03] and other Hematologic [B06];
- – Mitteln zur Behandlung und Vorbeugung von Erkrankungen des kardiovaskulären Systems [C]; - agents for the treatment and prevention of diseases of the cardiovascular system [C]; insbesondere Mitteln zur Herzherapie [C01], Antihypertonika [C02], Diuretika [C03], peripheren Vasodilatatoren [C04], Vasoprotektoren [C05], Antihypotonika [C06A], β-Adrenozeptor-Antagonisten [C07], Calciumkanalblockern [C08], Mitteln mit Wirkung auf das Renin-Angiotensin-System [C09] und Lipid senkenden Mitteln [C10]; in particular means for Herzherapie [C01], anti-hypertensives [C02], diuretics [C03], peripheral vasodilators [C04], vasoprotectors [C05], antihypotensives [C06A], β-adrenoceptor antagonist [C07], calcium channel blockers [C08], means with acting on the renin-angiotensin system [C09] and lipid lowering agents [C10];
- – Dermatika [D]; - Dermatological [D]; insbesondere Antimykotika zur systemischen Anwendung [D01B], Antipsoriatika zur systemischen Anwendung [D05B], Aknemittel zur systemischen Anwendung [D10B]; in particular antifungals for systemic use [D01B], antipsoriatics for systemic use [D05B], anti-acne preparations for systemic use [D10B];
- – Mitteln zur Behandlung und Vorbeugung von Erkrankungen des Urogenitalsystems und Sexualhormonen [E]; - agents for the treatment and prevention of diseases of the genitourinary system and sex hormones [E]; insbesondere gynäkologischen Antiinfektiva und Antiseptika [G01], Wehen fördernden Mitteln [G02A], Wehen hemmenden Sympathomimetika [G02CA], Prolactinhemmern [G02CB], hormonalen Kontrazeptiva zur systemischen Anwendung [G03] und Urologika [G04]; particularly gynecological antiinfectives and antiseptics [G01], pains [G02A] labor retardant sympathomimetic [G02CA], prolactin inhibitors inhibitors [G02CB], hormonal contraceptives for systemic use [G03] and Urologicals [G04];
- – systemischen Hormonpräparaten ausschließlich Sexualhormonen und Insulinen [H]; - systemic hormone preparations exclusively sex hormones and insulins [H]; insbesondere Hypophysen- und Hypothalamushormonen und Analoga [H01], Corticosteroiden zur systemischen Anwendung [H02], Schilddrüsenpräparaten [H03], Pankreashormonen [H04], und Mitteln zur Regulation der Calciumhomöostase [H05]; particularly pituitary and hypothalamic hormones and analogues [H01] corticosteroids for systemic use [H02], thyroid preparations [H03], pancreatic hormones [H04], and means for regulation of calcium homeostasis [H05];
- – Antiinfektiva zur systemischen Anwendung [J]; - anti-infectives for systemic use [J]; insbesondere Antibiotika zur systemischen Anwendung [J01], Antimykotika zur sytemischen Anwendung [J02], Mitteln gegen Mykobakterien [J04], antiviralen Mitteln zur systemischen Anwendung [J05], Immunsera und Immunglobulinen [J06], und Impfstoffen [J07]); particularly antibiotics for systemic use [J01], antimycotics for sytemischen use [J02], against mycobacteria [J04], anti-viral agents for systemic use [J05], immune sera and immunoglobulins [J06], and vaccines [J07]);
- – antineoplastischen und immunmodulierenden Mitteln [L] (insbesondere antineoplastischen Mitteln [L01], Mitteln zur endokrinen Therapie [L02], Immunstimulantien [L03] und Immunsuppressiva [L04]; - antineoplastic and immunomodulating agents [L] (especially antineoplastic agents [L01], agents for endocrine therapy [L02], immunostimulants [L03] and immunosuppressive agents [L04];
- – Mitteln zur Behandlung und Vorbeugung von Erkrankungen der Muskeln und des Skelettsystems [M]; - agents for the treatment and prevention of diseases of the muscles and the skeletal system [M]; insbesondere Antiphlogistika und Antirheumatika [M01], peripher wirkenden Muskelrelaxanzien [M03A], direkt wirkenden Muskelrelaxanzien [M03C], Gichtmitteln [M04] und Mitteln zur Behandlung von Knochenerkrankungen [M05]; especially antiinflammatories and antirheumatics [M01], peripherally acting muscle relaxants [M03A], direct-acting muscle relaxants [M03C], gout agents [M04], and agents for treating bone diseases [M05];
- – Mitteln zur Behandlung und Vorbeugung von Erkrankungen des Nervensystems [N]; - agents for the treatment and prevention of diseases of the nervous system [N]; insbesondere Salicyclsäure und ihren Derivaten [N02BA], Pyrazolonen [N02BB], Aniliden [N02BE], Mutterkorn-Alkaloiden [N02CA], Corticosteroid-Derivaten [N02CB], selektiven Serotonin-5HT 1 -Agonisten [N02CC], Hydantoin-Derivaten [N03AB], Oxazolidin-Derivaten [N03AC], Succinimid-Derivaten [N03AD], Carboxamid-Derivaten [N03AF], Fettsäure-Derivaten [N03AG], Antiparkinsonmitteln [N04]), Antipsychotika [N05A], Antidepressiva [N06A], Antidementiva [N06D], Parasympathomimetika [N07A] und Antivertiginosa [N07C]; in particular salicylic acid and its derivatives [N02BA] pyrazolones [N02BB] anilides [N02BE], ergot alkaloids [N02CA] corticosteroid derivatives [N02CB], selective serotonin 5HT 1 agonist [N02CC], hydantoin derivatives [N03AB] , oxazolidine derivatives [N03AC] succinimide derivatives [N03AD] carboxamide derivatives [N03AF], fatty acid derivatives [N03AG], anti-Parkinson agents [N04]), antipsychotics [N05A], antidepressants [N06A], anti-dementia drugs [N06D], parasympathomimetics [N07A] and antivertiginous [N07C];
- – antiparasitären Mitteln, Insektiziden und Repellenzien [P]; - antiparasitic agents, insecticides and repellents [P]; insbesondere Mitteln gegen Protozoen-Erkrankungen [P01], Antihelmintika [P02] und Mitteln gegen Ektoparasiten einschließlich Antiscabiosa, Insektiziden und Repellenzien [P03]; particular agents against protozoal diseases [P01], anthelmintics [P02] and agents against ectoparasites including scabicides, insecticides and repellents [P03];
- – Mitteln zur Behandlung und Vorbeugung von Erkrankungen des Respirationstrakts [R]; - agents for the treatment and prevention of diseases of the respiratory tract [R]; insbesondere Rhinologika [R01], Hals- und Rachentherapeutika [R02], Mitteln bei obstruktiven Atemwegserkrankungen [R03], Expektoranzien ausschließlich Kombinationen mit Antitussiva [R05C] und Antihistaminika zur systemischen Anwendung [R06]; in particular nasal preparations [R01], neck and throat infections [R02], means for obstructive airway diseases [R03], expectorants, excluding combinations with antitussives [R05C] and antihistamines for systemic use [R06];
- – Mitteln zur Behandlung und Vorbeugung von Erkrankungen der Sinnesorgane [S]; - agents for the treatment and prevention of diseases of the sensory organs [S]; insbesondere Otologika [S02]; in particular otologicals [S02];
- – Allgemeinen Diätetika [V06] und Radiotherapeutika [V10], - general diet [V06] and radiotherapeutic agents [V10]
- Bevorzugt enthält die erfindungsgemäße Darreichungsform eine Substanz (A) oder mehrere Substanzen (A) ausgewählt aus der Gruppe bestehend aus 4-Aminomethylbenzoesäure, Abacavir, Abamectin, Abciximab, Abibendan, Abrin, Acamprosat, Acarbose, Acebutolol, Aceclidin, Aceclofenac, Acediasulfon, Acemetacin, Acenocoumarol, Acetazolamid, Acetessigsäure, Acetyl Digoxin, Acetylandromedol, Acetylcystein, β-Acetyldigoxin, Acetylhistamin, Acetylsalicylsäure, Acetylthiocholin, Aciclovir, Acipimox, Acitretin, Aclarubicin, Aconitin, Acriflavinium Chlorid, Acrivastin, Actinoquinol, Acylaminopenicillin, Adalimumab, Adapalen, Adefovir, Adefovir Dipivoxil, Adenosin, Adenosinphosphat, Adenosintriphosphat, Adipiodon, Adrenalin, Aescin, Agalsidase Alfa, Agalsidase Beta, Agaricinsäure, Ajmalin, Alanin, Albendazol, Alcuronium, Aldesleukin, Aldosteron, Alemtuzumab, Alendronsäure, Alfacalcidol, Alfuzosin, Algeldrat F, Alitretinoin, Alizaprid, Allantoin F, Allopurinol, Allylisorhodanat, Almasilat F, Almo Preferably, the inventive dosage form contains a substance (A) or more substances (A) selected from the group consisting of 4-aminomethyl benzoic acid, abacavir, abamectin, abciximab, Abibendan, abrin, acamprosate, acarbose, acebutolol, aceclidine, aceclofenac, acediasulfone, acemetacin, acenocoumarol, acetazolamide, acetoacetic acid, acetyl digoxin, Acetylandromedol, acetylcysteine, β-acetyldigoxin, Acetylhistamin, acetylsalicylic acid, acetylthiocholine, acyclovir, acipimox, acitretin, aclarubicin, aconitine, Acriflavinium chloride, acrivastine, Actinoquinol, Acylaminopenicillin, adalimumab, adapalene, adefovir, adefovir dipivoxil , adenosine, adenosine phosphate, adenosine triphosphate, Adipiodon, adrenaline, aescin, agalsidase Alfa, agalsidase beta, agaric, ajmalin, alanine, albendazole, alcuronium, aldesleukin, aldosterone, alemtuzumab, alendronate, alfacalcidol, alfuzosin, Algeldrat F, alitretinoin, alizaprid, allantoin F , allopurinol, Allylisorhodanat, almasilate F, Almo triptan, α-Acetyldigoxin, Alprenolol, Alprostadil, Alteplase, Aluminiumglycinat F, Aluminiumhydroxyd F, Aluminiumphosphat F, Aluminiumtriformiat, Amantadin, Ambazon, Ambroxol, Ambutonium Bromid, Ameisensäure, Amicacin, Amidefrin, Amidotrizoesäure, Amifostin, Amikacin, Amilorid, Amino-Essigsäure, Aminoglutethimid, Aminophyllin, Aminoquinurid, Amiodaron, Amisulprid, Amitriptylin, Amitryptilin, Amlodipin, Amorolfin, Amoxicillin, Amphotericin B, Ampicillin, Amprenavir, Amylmetacresol, Amylnitrit, Anagrelid, Anakinra, Anastrozol, Ancrod, Anistreplase, Antazolin, Antithrombin III, Apomorphin, Apraclonidin, Aprepitant, Aprindin, Aprotinin, Arcitumomab, Arginin, Aripiprazole, Arsen Trioxid, Artemether, Articain, Ascorbinsäure, Asparagin, L-Asparaginase, Asparaginsäure, Atazanavir, Atenolol, Atorvastatin, Atosiban, Atovaquon, Atracurium, Atracurium Besilat, Atropin, Auranofin, Azapropazon, Azathioprin, Azelainsäure, Azelastin, Azidothymidin, Azithromycin, Azlocillin, Aztreonam, N2-Alanyl triptan, α-acetyldigoxin, alprenolol, alprostadil, alteplase, aluminum glycinate F, aluminum hydroxide F, aluminum phosphate, F, aluminum triformate, amantadine, ambazone, ambroxol, Ambutonium bromide, formic acid, amikacin, Amidefrin, diatrizoic acid, amifostine, amikacin, amiloride, amino-acetic acid, aminoglutethimide, aminophylline, Aminoquinurid, amiodarone, amisulpride, amitriptyline, amitriptyline, amlodipine, amorolfine, amoxicillin, amphotericin B, ampicillin, amprenavir, amylmetacresol, amyl nitrite, anagrelide, anakinra, anastrozole, ancrod, anistreplase, antazoline, antithrombin III, apomorphine, apraclonidine, aprepitant, aprindine, aprotinin, Arcitumomab, arginine, Aripiprazole, arsenic trioxide, artemether, articaine, ascorbic acid, asparagine, L-asparaginase, aspartic acid, atazanavir, atenolol, atorvastatin, atosiban, atovaquone, atracurium, atracurium besilate, atropine, auranofin, azapropazone, azathioprine, azelaic acid, azelastine, azidothymidine, azithromycin, azlocillin, aztreonam, N2-alanyl levoglutamid, p-Aminosalicylsäure, levoglutamid, p-aminosalicylic acid,
Bacampicillin, Bacitracin, Baclofen, Balsalazid, Bambuterol, Bamethan, Bamipin, Barbexaclon, Bariumsulfat F, Barnidipin, Basiliximab, Batroxobin, Becaplermin, Beclometason, Bedamustin, Befunolol, Bemiparin, Benactyzin, Benazepril, Bencyclan, Bendazac, Bendroflumethiazid, Benproperin, Benserazid, Benzaserid, Benzathin, Benzatropin, Benzbromaron, Benzocain, Benzoylperoxid, Benzyclan, Benzydamin, Benzylpenicillin, Benzylphenylglykolat, Betacaroten, Betahistidin, Betahistin, Betamethason, Betanechol, Betaxolol, Bethanechol Chlorid, Betiatid, Bexaroten, Bezafibrat, Bibenzonium Bromid, Bicalutamid, Bicisat, Bifonazol, Bimatoprost, Biperiden, Bisoprolol, Bivalirudin, Bleomycin, Blutgerinnungsfaktor VII, VIII, IX, X, XIII, Bornapin, Bomaprin, Bortezomib, Bosentan, Botulinum Toxin Typ B, Brimonidin, Brinzolamid, Brivudin, Bromhexin, Bromocriptin, Bromperidol, Brompheniramin, Brotizolam, Budesonid, Budipin, Bufexamac, Buflomedil, Bumetanid, Bunazosin, Buphenin, Bupivacain, Bupranolol, Bupropion, Bacampicillin, bacitracin, baclofen, balsalazide, bambuterol, bamethan, bamipine, barbexaclone, barium F, barnidipine, basiliximab, batroxobin, becaplermin, beclomethasone, Bedamustin, befunolol, Bemiparin, benactyzine, benazepril, bencyclane, bendazac, bendroflumethiazide, benproperine, benserazide, Benzaserid , benzathine, benzatropine, benzbromarone, benzocaine, benzoyl peroxide, Benzyclan, benzydamine, benzylpenicillin, Benzylphenylglykolat, betacarotene, betahistidine, betahistine, betamethasone, Bethanechol, betaxolol, bethanechol chloride, Betiatid, bexarotene, bezafibrate, Bibenzonium bromide, bicalutamide, Bicisate, bifonazole, bimatoprost , biperiden, bisoprolol, bivalirudin, bleomycin, blood clotting factor VII, VIII, IX, X, XIII, Bornapin, Bomaprin, bortezomib, bosentan, botulinum toxin type B, brimonidine, brinzolamide, brivudine, bromhexine, bromocriptine, bromperidol, brompheniramine, brotizolam, budesonide , budipine, bufexamac, buflomedil, bumetanide, bunazosine, buphenin, bupivacaine, bupranolol, bupropion, Buserelin, Buspiron, Busulfan, Butalamin, Butanilicain, Butenafin, Butetamat, Butinolin, Butizid, Butylscopolaminium, Buserelin, buspirone, busulfan, butalamine, butanilicaine, Butenafine, Butetamat, Butinolin, butizide, butylscopolaminium,
5-Chlorcarvacrol, C1-Esterase-Inhibitor, Cabergolin, Cadexomer Jod, Cafedrin, Calcipotriol, Calcitonin, Calcitriol, Camylofin, Candesartan Cilexetil, Canrenoinsäure, Capecitabin, Capreomycin, Capsaicin, Captopril, Carazolol, Carbaldrat F, Carbamazepin, Carbasalat Calcium, Carbenoxolon, Carbidopa, Carbimazol, Carbinoxamin, Carboplatin, Carglumic Acid, Carglumsäure, Carmustin, Caroverin, Carteolol, Carvedilol, Caspofungin, Cefaclor, Cefadroxil, Cefalexin, Cefaloridin, Cefamandol, Cefazolin, Cefdinir, Cefepim, Cefetametpivotil, Cefixim, Cefodizim, Cefoperazon, Cefotaxim, Cefotiam, Cefoxitin, Cefpirom, Cefpodoxim, Cefpodoximproxetil, Cefprozil, Ceftazidim, Ceftibuten, Ceftizoxim, Ceftriaxon, Cefuroxim, Celecoxib, Celiprolol, Certoparin, Cetirizin, Cetrimid, Cetrimonium Bromid, Cetrorelix, Cetuximab, Cetylpiridinium, Chenodeoxycholsäure, Chinidin, Chinin, Chinin-Eisen-Citrat F, Chinin-Tannat F, Chlorambucil, Chloramphenicol, Chlorbutinol, Chlorhexidin, Chlormidazol, Chlorobutanol, Chloro 5-Chlorcarvacrol, C1-inhibitor, cabergolin, cadexomer iodine, cafedrine, calcipotriol, calcitonin, calcitriol, camylofine, candesartan cilexetil, Canrenoinsäure, capecitabine, capreomycin, capsaicin, captopril, carazolol, Carbaldrat F, carbamazepine, carbasalate calcium, carbenoxolone, carbidopa, carbimazole, carbinoxamine, carboplatin, Carglumic Acid, Carglumic acid, carmustine, caroverine, carteolol, carvedilol, caspofungin, cefaclor, cefadroxil, cefalexin, cefaloridine, cefamandole, cefazolin, cefdinir, cefepime, Cefetametpivotil, cefixime, cefodizime, cefoperazone, cefotaxime, cefotiam , cefoxitin, cefpirome, cefpodoxime, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, celecoxib, celiprolol, certoparin, cetirizine, cetrimide, cetrimonium bromide, cetrorelix, cetuximab, Cetylpiridinium, chenodeoxycholic acid, quinidine, quinine, quinine-iron citrate F, quinine tannate F, chlorambucil, chloramphenicol, Chlorbutinol, chlorhexidine, chlormidazole, chlorobutanol, chloro quin, Chloroxylenol, Chlorphenamin, Chlorphenesin, Chlorphenoxamin, Chlorpromazin, Chlorprotheaxin, Chlorprothixen, Chlortalidon, Chlortetracyclin, Chlorzoxazon, Cholin, Chondroitinsulfat, Choriogonadotropin Alfa, Choriongonadotropin, Chrysarobin, Chymotrypsin, Cicletanin, Ciclopirox, Ciclosporin, Cidofovir, Cilastatin, Cilazapril, Cimetidin, Cinacalcet, Cinchocain, Cinnarizin, Cinolazepam, Ciprofloxacin, Cisaprid, Cisatracurium Besilat, Cisplatin, Citalopram, Citicolin, Cladribin, Clarithromycin, Clavulansäure, Clemastin, Clenbuterol, Clindamycin, Clioquinol, Clobetasol, Clobetason, Clobutinol, Clocortolon, Clodronsäure, Clofibrat, Clomifen, Clomipramin, Clonazepam, Clonidin, Clopamid, Clopidogrel, Clostebolacetat, Clostridium Botulinum, Clotrimazol, Cloxiquin, Clozapin, Cocarboxylase, Colchicin, Colecalciferol, Colesevelam, Colestipol, Colestyramin, Colfosceril Palmitat, Colistin, Collyrium Zinci F, Corticorelin, Corticotrophin, Cortison, Cresol, Croconazol, Cromoglicinsäure, Crot quin, chloroxylenol, chlorpheniramine, chlorphenesin, chlorphenoxamine, chlorpromazine, Chlorprotheaxin, chlorprothixene, chlorthalidone, chlortetracycline, chlorzoxazone, choline, chondroitin, choriogonadotropin alfa, chorionic gonadotropin, Chrysarobin, chymotrypsin, cicletanine, Ciclopirox, ciclosporin, cidofovir, cilastatin, cilazapril, cimetidine, cinacalcet , cinchocaine, cinnarizine, Cinolazepam, ciprofloxacin, cisapride, cisatracurium besilate, cisplatin, citalopram, citicoline, cladribine, clarithromycin, clavulanic acid, clemastine, clenbuterol, clindamycin, clioquinol, clobetasol, clobetasone, clobutinol, clocortolone, clodronic acid, clofibrate, clomiphene, clomipramine, clonazepam, clonidine, clopamide, clopidogrel, clostebol, Clostridium botulinum, clotrimazole, Cloxiquin, clozapine, cocarboxylase, colchicine, colecalciferol, colesevelam, colestipol, cholestyramine, Colfosceril palmitate, colistin, collyrium Zinci F, corticorelin, corticotrophin, cortisone, cresol, croconazole, cromolyn Crot amiton, Cryofluoran, Cumarin, Cyanamid, Cyanocobalamin, Cyclizin, Cyclobutyrol, Cyclopentolat, Cyclophosphamid, Cycloserin, Cyproheptadin, Cyproteron, Cystein, Cytarabin, Cytarabine, Amiton, Cryofluoran, coumarin, Cyanamid, cyanocobalamin, cyclizine, Cyclobutyrol, cyclopentolate, cyclophosphamide, cycloserine, cyproheptadine, cyproterone, cysteine, cytarabine, cytarabine,
2,4-Dichlorbenzylalkohol, 2-Diethylaminoethanol, Dacarbazin, Daclizumab, Dactinomycin, Dalfopristin, Dalteparin, Danaparoid, Danazol, Dantrolen, Dapiprazol, Dapson, Darbepoetin Alfa, Darifenacin, Daunorubicin, Deamol, Deanolace, Decarbazin, Dectaflur F, Deferipron, Deferoxamin, Delapril, Demeclocyclin, Denaverin, Depreotid, Dequalinium, Desfluran, Desipramin, Desirudin, Deslanosid, Desloratadin, Desmeninol, Desmopressin, Desogestrel, Desoximetason, Desoxyribonuclease, Detajmium, Dexamethason, Dexchlorpheniramin, Dexibuprofen, Dexketoprofen, Dexrazoxan, Dextran, Dextromethorphan, Diacerein, Diacetylmorphin, Dibenzepin, Dibotermin Alfa, Diclofenac, Diclofenamid, Didanosin, Dienestrol, Dienogest, Diethylstilbestrol, Difloxacin, Diflucortolon, Diflunisal, Digitoxin, Digoxin, Dihydralazin, Dihydroergocornin, Dihydroergocristin, Dihydroergocryptin, Dihydroergotamin, Dihydroergotoxin, Dihydrotachysterol, Diisopropylamin, Dikaliumclorazepat, Diltiazem, Dimenhydrinat, Dimepranol, Dimercaprol, D 2,4-dichlorobenzyl, 2-diethylaminoethanol, dacarbazine, daclizumab, dactinomycin, dalfopristin, dalteparin, danaparoid, danazol, dantrolene, dapiprazole, dapsone, darbepoetin alfa, darifenacin, daunorubicin, Deamol, deanolace, decarbazine, dectaflur F, deferiprone, deferoxamine, delapril, demeclocycline, Denaverine, depreotide, dequalinium, desflurane, desipramine, desirudin, deslanoside, desloratadine, Desmeninol, desmopressin, desogestrel, desoximetasone, deoxyribonuclease, Detajmium, dexamethasone, dexchlorpheniramine, dexibuprofen, dexketoprofen, dexrazoxane, dextran, dextromethorphan, diacerein, diacetylmorphine, dibenzepin, dibotermin Alfa, diclofenac, diclofenamide, didanosine, dienestrol, dienogest, diethylstilbestrol, difloxacin, diflucortolone, diflunisal, digitoxin, digoxin, dihydralazine, dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydroergotamine, dihydroergotoxine, dihydrotachysterol, diisopropylamine, chlorazepate, diltiazem, dimenhydrinate, Dimepranol , dimercaprol, D imethylsulfoxid, Dimetinden, Dinatriumselenit, Dinoprost, Dinoproston, Diosmin, Diphenhydramin, Diphenoxylat, Diphenylpyralin, Dipivefrin, Diprophyllin, Dipyridamol, Disopyramid, Distickstoffmonoxid, Distigmin, Disulfiram, Dithranol, Dixyrazin, D-Norpseudoephedrin, Dobesilat Calcium, Dobutamin, Docetaxel, Dofetilid, Dolasetron, Domperidon, Donepezil, Dopamin, Dopexamin, Dornase Alfa, Dorzolamid, Dosulepin, Doxapram, Doxazosin, Doxepin, Doxorubicin, Doxycyclin, Doxylamin, Drofenin, Droperidol, Drospirenon, Drotrecogin Alfa, Duloxetine, Dutasterid, Dydrogesteron, N,N'-Dihydroxymethyl-Harnstoff, imethylsulfoxid, dimetindene, Dinatriumselenit, dinoprost, dinoprostone, Diosmin, diphenhydramine, diphenoxylate, diphenylpyraline, dipivefrin, diprophylline, dipyridamole, disopyramide, nitrous oxide, distigmine, disulfiram, dithranol, dixyrazine, D-norpseudoephedrine, dobesilate calcium, dobutamine, docetaxel, dofetilide, dolasetron , domperidone, donepezil, dopamine, dopexamine, dornase Alfa, dorzolamide, dosulepin, doxapram, doxazosin, doxepin, doxorubicin, doxycycline, doxylamine, Drofenin, droperidol, drospirenone, drotrecogin alfa, Duloxetine, dutasteride, dydrogesterone, N, N'-dihydroxymethyl Urea,
Ebastin, Econazol, Ecothiopat Jodid, Efalizumab, Efavirenz, Eflornithin, Eisen III-ammonium citrat F, Eisenoxid superparamagnetisch, Elcatonin, Eletriptan, Emedastin, Emepronium, Emepronium Carragenat, Emetin, Emtricitabine, Enalapril, Enalaprilat, Enfluran, Enfuvirtid, Enoxacin, Enoxapann, Entacapon, Ephedrin, Ephedrin Racephedrin, Epinastin, Epinephrin, Epirubicin, Epoetin Alfa, Epoetin Beta, Epoetin Delta, Epoprostenol, Eprazinon, Eprosartan, Eptacog Alfa, Eptifibatid, Eptotermin Alfa, Erdostein, Ergocalciferol, Ergometrin, Ergotamid, Ertapenem, Erythromycin, Escitalopram, Esmolol, Esomeprazol, Estradiol, Estramustin, Estriol, Estron, Etacrynsäure, Etamivan, Etanercept, Ethacridin, Ethambutol, Ethaverin, Ethinylestradiol, Ethisteron, Ethosuximid, Etidronsäure, Etilefrin, Etodolac, Etofenamat, Etofibrat, Etofyllin, Etomidat, Etonogestrel, Etoposid, Etoricoxib, Exametazim, Exemestan, Ezetimib, Ebastine, econazole, ecothiopate iodide, efalizumab, efavirenz, eflornithine, ferric ammonium citrate F, iron oxide superparamagnetic, elcatonin, eletriptan, emedastine, emepronium, emepronium Carragenat, emetine, emtricitabine, enalapril, enalaprilat, enflurane, enfuvirtide, enoxacin, Enoxapann, entacapone, ephedrine, ephedrine Racephedrin, epinastine, epinephrine, epirubicin, epoetin alfa, epoetin beta, epoetin delta, epoprostenol, Eprazinon, eprosartan, eptacog Alfa, eptifibatide, eptotermin Alfa, erdosteine, ergocalciferol, ergonovine, Ergotamid, ertapenem, erythromycin, escitalopram, esmolol, esomeprazole, estradiol, estramustine, estriol, estrone, ethacrynic acid, etamivan, etanercept, ethacridine, ethambutol, ethaverine, ethinyl estradiol, ethisterone, ethosuximide, etidronic acid, etilefrine, etodolac, etofenamate, etofibrate, etofylline, etomidate, etonogestrel, etoposide, etoricoxib, Exametazim, exemestane, ezetimibe,
3-Fluortyrosin, Famciclovir, Famotidin, Felbamat, Felbinac, Felodipin, Fenbufen, Fendilin, Fenofibrat, Fenoterol, Fenticonazol, Fexofenadin, Fibrinogen, Fibrinolysin, Filgrastim, Finasterid, Flavoxat, Flecainid, Flucloxacillin, Fluconazol, Fludarabin, Fludeoxyglucose [ 18 F], Fludrocortison, Flufenaminsäure, Flumazenil, Flumetason, Flunarizin, Flunisolid, Fluocinolon Acetonid, Fluocinonid, Fluocortolon, Fluophenozin, Fluorescein Dilaurat, Fluorescein-Natrium, Fluorometholon, Fluorouracil, Fluorphosphorsäure, Fluorsilan, Fluoxetil, Fluoxetin, Flupentixol, Fluphenazin, Flupirtin, Flupredniden, Flurbiprofen, Flutamid, Fluticason, Flutrimazol, Fluvastatin, Fluvoxamin, Folinsäure, Follitropin Alfa, Follitropin Beta, Folsäure, Fomepizol, Fomivirsen, Fondaparinux, Formestan, Formoterol, Fosamprenavir, Foscarnet, Fosfestrol, Fosfomycin, Fosinopril, Fosphenytoin, Fotemustin, Framycetin, Framycetin, Frovatriptan, Fulvestrant, Furosemid, Fusafungin, Fusidinsäure, Fytinsäure, 3-fluorotyrosine, famciclovir, famotidine, felbamate, felbinac, felodipine, fenbufen, fendiline, fenofibrate, fenoterol, fenticonazole, fexofenadine, fibrinogen, fibrinolysin, filgrastim, finasteride, flavoxate, flecainide, flucloxacillin, fluconazole, fludarabine, fludeoxyglucose [18 F] fludrocortisone, flufenamic, flumazenil, Flumetason, flunarizine, flunisolide, fluocinolone acetonide, fluocinonide, fluocortolone, fluphenazine, fluorescein dilaurate, fluorescein sodium, fluorometholone, fluorouracil, fluorine phosphoric acid, fluorosilane, Fluoxetil, fluoxetine, flupentixol, fluphenazine, flupirtine, fluprednidene, flurbiprofen, flutamide, fluticasone, flutrimazole, fluvastatin, fluvoxamine, folinic acid, follitropin alpha, follitropin beta, folic acid, fomepizole, fomivirsen, fondaparinux, formestane, formoterol, fosamprenavir, foscarnet, fosfestrol, fosfomycin, fosinopril, fosphenytoin, fotemustine, framycetin, framycetin, frovatriptan, fulvestrant, furosemide, fusafungine, fusidic acid, phytic acid,
Gabapentin, Gadobensäure, Gadobutrol, Gadodiamid, Gadopentetsäure, Gadoteridol, Gadotersäure, Galantamin, Gallopamil, Ganciclovir, Ganirelix, Gatifloxacin, Gemcitabin, Gemfibrozil, Gentamicin, Gepefrin, Gestoden, Glatiramer, Glibenclamid, Glibomurid, Gliclazid, Glimepirid, Glipizid, Gliquidon, Glisoxepid, Glucagon, Glutamin, Glutaminsäure, Glycopyrronium, Glycopyrronium Bromid, Glycyrrhetinsäure, Gonadorelin, Goserelin, Gramicidin, Granisetron, Grepafloxacin, Griseofulvin, G-Strophanthin, Guajacol, Guanethidin, Guanfacin, Gabapentin, gadobenate, Gadobutrol, gadodiamide, gadopentetic acid, gadoteridol, gadoteric acid, galantamine, gallopamil, ganciclovir, ganirelix, gatifloxacin, gemcitabine, gemfibrozil, gentamicin, Gepefrin, gestodene, glatiramer, glibenclamide, Glibomurid, gliclazide, glimepiride, glipizide, gliquidone, glisoxepid, glucagon, glutamine, glutamic acid, glycopyrronium, glycopyrronium bromide, glycyrrhetinic acid, gonadorelin, goserelin, gramicidin, granisetron, grepafloxacin, griseofulvin, ouabain, guaiacol, guanethidine, guanfacine,
13 C-Harnstoff, 4-Hydroxybuttersäure, Halcinonid, Halofantrin, Halometason, Halopetidol, Halothan, Häm, Hämatoporphyrin, Heparin, Hepatitis B Vaccine, Heptaminol, Hexobarbital, Hexobendin, Hexoprenalin, Histamin, Histidin, Homatropin, Homofenazin, Humanalbumin, Hyaluronidase, Hydralazin, Hydrastinin, Hydrochinon, Hydrochlorothiazid, Hydrocortison, Hydrotalcit F, Hydroxocobalamin, Hydroxycarbamid, Hydroxychloroquin, Hydroxycin, Hydroxylamin, Hydroxyprogesteron, Hydroxyzin, Hymecromon, 13 C-urea, 4-hydroxybutyric acid, halcinonide, halofantrine, halometasone, Halopetidol, halothane, heme, hematoporphyrin, heparin, Hepatitis B Vaccine, heptaminol, hexobarbital, hexobendine, hexoprenaline, histamine, histidine, homatropine, homofenazine, human albumin, hyaluronidase, hydralazine , hydrastinine, hydroquinone, hydrochlorothiazide, hydrocortisone, hydrotalcite F, hydroxocobalamin, hydroxycarbamide, hydroxychloroquine, hydroxycine, hydroxylamine, hydroxyprogesterone, hydroxyzine, hymecromone,
Ibandronsäure, Ibopamin, Ibritumomab Tiuxetan, Ibuprofen, Ibutilid, Idarubicin, Ifosfamid, Iloprost, Imatinib, Imatinib Mesilate, Imidapril, Imiglucerase, Imipenem, Imipramin, Imiquimod, Immunocyanin, Indanazolin, Indapamid, Indinavir, Indium Chlorid [ 111 In], Indobufen, Indometacin, Indoramin, Infliximab, Inosin, Insulin, Insulin Aspart, Insulin Detemir, Insulin Glargin, Insulin Glulisine, Insulin Lispro, Interferon Alfa, Interferon Alfa-2b, Interferon Alfacon-1, Interferon Beta, Interferon Beta-1a, Interferon Beta-1b, Interferon Gamma, Iobitridol, Iod, Iodamid, Iodixanol, Ioflupan [ 123 I], Iohexol, Iomeprol, Iopamidol, Iopentol, Iopromid, Iosarcol, Iotrolan, Iotroxinsäure, Ioversol, Ioxaglinsäure, Ioxitalaminsäure, Ipatropium, Irbesartan, Irinotecan, Irinotecan, Isepamicin, Isoaminil, Isoconazol, Isofluran, Isoleucin, Isoniazid, Isonicotinsäure, Isoprenalin, Isosorbid, Isospagluminsäure, Isotretinoin, Isoxsuprin, Isradipin, Itraconazol, Ibandronic acid, ibopamine, ibritumomab tiuxetan, ibuprofen, ibutilide, idarubicin, ifosfamide, iloprost, imatinib, imatinib Mesilate, imidapril, imiglucerase, imipenem, imipramine, imiquimod, Immunocyanin, Indanazoline, indapamide, indinavir, indium chloride [111 In], indobufen, indometacin , indoramin, infliximab, inosine, insulin, insulin aspart, insulin detemir, insulin glargine, insulin glulisine, insulin lispro, interferon alfa, interferon alfa-2b, interferon alfacon-1, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, Iobitridol, iodine, iodamide, iodixanol, ioflupane [123 I], iohexol, iomeprol, iopamidol, iopentol, iopromide, iosarcol, iotrolan, iotroxic acid, ioversol, ioxaglic acid, Ioxitalaminsäure, Ipatropium, irbesartan, irinotecan, irinotecan, isepamicin, Isoaminil , isoconazole, isoflurane, isoleucine, isoniazid, isonicotinic, isoprenaline, isosorbide, Isospagluminsäure, isotretinoin, isoxsuprine, isradipine, itraconazole,
Josamycin, josamycin,
Kaliumpermanganat, Kallidinogenase, Kanamycin, Kawain, Kebuzon, Ketamin, Ketoconazol, Ketoprofen, Ketorolac, Ketotifen, Kollagenase, Kreosot, Potassium permanganate, kallidinogenase, kanamycin, kawain, kebuzone, ketamine, ketoconazole, ketoprofen, ketorolac, ketotifen, collagenase, creosote,
Labetalol, Lacidipin, Lactitol, Lamivudin, Lamottigin, Lanreotid, Lansoprazol, Laronidase, Latanoprost, Leflunomide, Lenograstim, Lepirudin, Lercanidipin, Letrozol, Leucin, Leuprorelin, Levallorphan, Levamisol, Levetiracetam, Levobunolol, Levobupivacain, Levocabastin, Levocetirizin, Levodopa, Levofloxacin, Levofolinat Calcium, Levomepromazin, Levomethadyl, Levonorgestrel, Levopropylhexedrin, Levosimendan, Levothyroxin, Lidocain, Lincomycin, Lindan, Linezolid, Liothyronin, Lisinopril, Lisurid, Lobelin, Lodoxamid, Lofepramin, Lomefloxacin, Lomustin, Lonazolac, Loperamid, Lopinavir, Loratadin, Lorazepam Oxid, Lornoxicam, Losartan, Lovastatin, Lumefantrin, Lutropin Alfa, Lymecyclin, Lynestrenol, Lypressin, Lysin, Labetalol, lacidipine, lactitol, lamivudine, Lamottigin, lanreotide, lansoprazole, laronidase, latanoprost, leflunomide, lenograstim, lepirudin, lercanidipine, letrozole, leucine, leuprorelin, levallorphan, levamisole, levetiracetam, levobunolol, levobupivacaine, levocabastine, levocetirizine, levodopa, levofloxacin, Levofolinat calcium, levomepromazine, levomethadyl, levonorgestrel, Levopropylhexedrin, levosimendan, levothyroxine, lidocaine, lincomycin, lindane, linezolid, liothyronine, lisinopril, lisuride, lobeline, lodoxamide, lofepramine, lomefloxacin, lomustine, lonazolac, loperamide, lopinavir, loratadine, lorazepam oxide, lornoxicam, losartan, lovastatin, lumefantrine, lutropin alfa, lymecycline, lynestrenol, lypressin, lysine,
Magaldrat F, Magnesium Pidolat, Magnesium-L-Aspartat, Mangafodipir, Manidipin, Maprotilin, Mebendazol, Mebeverin, Meclofenoxat, Mecloxamin, Meclozin, Medrogeston, Medroxyprogesteron, Mefenaminsäure, Mefloquin, Megestrol, Melitracen, Melperol, Melperon, Melphalan, Memantin, Menadion, Mepacrin, Mepartricin, Mephenytoin, Mepindolol, Mepivacain, Mepyramin, Mequinol, Mercaptamin, Mercaptopurin, Meropenem, Mesalazin, Mesna, Mesterolon, Mesuximid, Metaclazepam, Metamizol, Metamphetamin, Metenolon, Metenolonacetat, Metformin, Methanthelinium, Methazolamid, Methenamin, Methionin, Methohexital, Methotrexat, 5-Methoxypsoralen, 8-Methoxypsoralen, Methyl 5-aminolevulinat, Methylbenactyzium Bromid, Methyldopa, Methylergometrin, Methylprednisolon, Methylrosanilinium, Methyltestosteron, Methylthionium Chlorid, Methysergid, Metildigoxin, Metipranolol, Metoclopramid, Metoprolol, Metrixen, Metronidazol, Mexiletin, Mezlocillin, Mianserin, Miconazol, Midodrin, Mifepriston, Miglitol, Miglustat, Milnacipran Magaldrate F, magnesium pidolate, magnesium L-aspartate, mangafodipir, manidipine, maprotiline, mebendazole, mebeverine, meclofenoxate, Mecloxamin, meclozine, medrogestone, medroxyprogesterone, mefenamic acid, mefloquine, megestrol, melitracen, Melperol, melperone, melphalan, memantine, menadione, mepacrine, mepartricin, mephenytoin, mepindolol, mepivacaine, mepyramine, Mequinol, Mercaptamin, mercaptopurine, meropenem, mesalazine, mesna, mesterolone, mesuximide, metaclazepam, dipyrone, methamphetamine, methenolone, Metenolonacetat, metformin, Methanthelinium, methazolamide, methenamine, methionine, methohexital, methotrexate, 5-methoxypsoralen, 8-methoxypsoralen, methyl 5-aminolevulinate, Methylbenactyzium bromide, methyldopa, methylergonovine, methylprednisolone, Methylrosanilinium, methyltestosterone, Methylthionium chloride, methysergide, metildigoxin, metipranolol, metoclopramide, metoprolol, Metrixen, metronidazole, mexiletine, mezlocillin, mianserin , miconazole, midodrine, mifepristone, miglitol, miglustat, milnacipran , Milrinon, Miltefosin, Minocyclin, Minoxidil, Mirtazapin, Misoprostol, Mitobronitol, Mitomycin, Mitotane, Mitoxantron, Mivacurium Chlorid, Mivacuronium, Mizolastin, Moclobemid, Moexipril, Molgramostim, Molsidomin, Mometason, Monochloressigsäure, Montelukast, Moroctocog Alfa, Moxaverin, Moxifloxacin, Moxonidin, Mupirocin, Mycophenolat Mofetil, , Milrinone, miltefosine, minocycline, minoxidil, mirtazapine, misoprostol, mitobronitol, mitomycin, mitotane, mitoxantrone, mivacurium chloride, mivacuronium, mizolastine, moclobemide, moexipril, molgramostim, molsidomine, mometasone, monochloroacetic acid, montelukast, Moroctocog Alfa, moxaverin, moxifloxacin, moxonidine , mupirocin, mycophenolate mofetil,
Nadifloxacin, Nadrolondecanonat, Nadroparin Calcium, Naftidrofuryl, Naftifin, Nalbuphin, Nalid, Nalmefen, Nalmexon, Naloxon, Naltrexon, Naluphin, Naphazolin, 2- Naphthol, Naproxen, Naratriptan, Naratriptan, Nateglinid, Natrium Aurothiomalat, Natrium Phenylbutyrate, Natriumfluorid, Natriumhyaluronat, Natriumiodid [ 131l I], Natriummolybdat [ 99 Mo], Natriumphenylbutyrat, N-Butyl-P-Aminobenzoat, N-Butylscopolaminiumbromid, Nebivolol, Nedocromil, Nefazodon, Nefopam, Nelfinavir, Neomycin, Neostigmin, Neostigmin Metilsulfat, Netilmicin, Nevirapin, N-Heptyl-2-Phenylglycinat, Nicardipin, Nicergolin, Nicethamid, Niclosamin, Nicoboxil, Nicorandil, Nicotin, Nicotinaldehyd, Nicotinamid, Nicotinresinat, Nicotinsäure, Nicotinsäureester, Nicotinylalkohol, Nifedipin, Nifluminsäure, Nifuratel, Nilvadipin, Nimesulid, Nimodipin, Nimorazol, Nimustatin, Nisoldipin, Nitrendipin, Nitric Oxide, Nitrofurantoin, Nitroglycerin, Nizatidin, N-Methylephedrin, Nonacog Alfa, Nonivamid, Noradrenalin, Norelgestromi Nadifloxacin, Nadrolondecanonat, nadroparin calcium, naftidrofuryl, naftifine, nalbuphine, nalide, nalmefene, nalmexone, naloxone, naltrexone, naluphine, naphazoline, 2- naphthol, naproxen, naratriptan, naratriptan, nateglinide, sodium aurothiomalate, sodium phenylbutyrate, sodium fluoride, sodium hyaluronate, sodium iodide [131l I], sodium [99 Mo], sodium phenylbutyrate, N-butyl-p-aminobenzoate, N-narcotic analgesics, nebivolol, nedocromil, nefazodone, nefopam, nelfinavir, neomycin, neostigmine, neostigmine Metilsulfat, netilmicin, nevirapine, N-heptyl 2-phenylglycinate, nicardipine, nicergoline, nicethamide, Niclosamin, Nicoboxil, nicorandil, nicotine, nicotinaldehyde, nicotinamide, Nicotinresinat, nicotinic acid, nicotinic acid, nicotinyl alcohol, nifedipine, niflumic acid, nifuratel, nilvadipine, nimesulide, nimodipine, nimorazole, Nimustatin, nisoldipine, nitrendipine, Nitric oxides, nitrofurantoin, nitroglycerine, nizatidine, N-methylephedrine, nonacog Alfa, nonivamide, noradrenaline, Norelgestromi n, Norepinephrin, Norethisteron, Norfenefrin, Norfloxacin, Norgestimat, Norgestrel, Nortriptylin, Noscapin, Nystatin, n, norepinephrine, norethisterone, norfenefrine, norfloxacin, norgestimate, norgestrel, nortriptyline, noscapine, nystatin,
Obidoxim Chlorid, Octafluoropropane, Octocog Alfa, Octodrin, Octreotid, Odansetron, Ofloxacin, Olaflur F, Olanzapin, Olmesartan Medoxomil, Olopatadin, Olsalazin, Omeprazol, Omoconazol, Ondansetron, Opipramol, Oral Cholera Vaccine, Orciprenalin, Orlistat, Omipressin, Orphenadrin, Oseltamivir, Osteogenes Protein-1: Bmp-7, Oxaprozin, Oxatomid, Oxcarbazepin, Oxedrintartrat, Oxetacain, Oxiconazol, Oxilofrin, Oxitropium, 2-Oxo-3-Methylbuttersäure, 2-Oxo-3-Methylvaleriansäure, 2-Oxo-3-Phenylpropionsäure, 2-Oxo-4-Methylvaleriansäure, Oxprenofol, Oxybuprocain, Oxybuprocain, Oxybutynin, Oxybutynin, Oxyfedrin, Oxymetazolin, Oxytetracyclin, Oxytocin, Obidoxime chloride, Octafluoropropane, Octocog Alfa, Octodrin, octreotide, odansetron, ofloxacin, Olaflur F, olanzapine, olmesartan medoxomil, olopatadine, olsalazine, omeprazole, omoconazole, ondansetron, opipramol, Oral Cholera Vaccine, Orciprenalin, orlistat, Omipressin, orphenadrine, oseltamivir, osteogenic protein-1: Bmp-7, oxaprozin, oxatomide, oxcarbazepine, Oxedrintartrat, Oxetacain, oxiconazole, oxilofrine, oxitropium, 2-oxo-3-methylbutyric acid, 2-oxo-3-methyl valeric acid, 2-oxo-3-phenylpropionic acid, 2 -oxo-4-methyl valeric acid, Oxprenofol, oxybuprocaine, oxybuprocaine, oxybutynin, oxybutynin, oxyfedrine, oxymetazoline, oxytetracycline, oxytocin,
Paclitaxel, Palinavir, Palivizumab, Pamidronsäure, Pancurmium, Pantoprazol, Papaverin, Paracetamol, Paraldehyd, Parecoxib, Paricalcitol, Parnaparin, Paromomycin, Paroxetin, Pefloxacin, Pegfilgrastim, Peginterferon Alfa, Pegvisomant, Pemetrexed, Penbutolol, Penciclovir, Penfluridol, Penicillamin, Penperidol; Paclitaxel, Palinavir, palivizumab, pamidronate Pancurmium, pantoprazole, papaverine, paracetamol, paraldehyde, parecoxib, paricalcitol, parnaparin, paromomycin, paroxetine, pefloxacin, pegfilgrastim, peginterferon alfa, pegvisomant, pemetrexed, penbutolol, penciclovir, penfluridol, penicillamine, Penperidol; Pentaerithrityl Tetranitrat, Pentamidin, Pentetrazol, Pentetreotid, Pentosan Polysulfat Natrium, Pentoxifyllin, Pentoxyverin, Perazin, Perchlorsäure, Perflenapent, Perflisopent, Perflutren, Pergolid, Perindopril, Perphenazin, Phenacetin, Phenamazid, Phenazon, Phenazopyridin, Pheniramin, Phenol, Phenolphthalein, Phenoxybenzamin, Phenoxymethylpenicillin, Phenprocoumon, Phentolamin, Phenylalanin, Phenylbutazon, Phenylephrin, Phenylpropanolamin, Phenyltoloxamin, Phenytoin, Phloroglucin, Pholedrin, Phthalylsulfathiazol, Physostigmin, Phytomenadion, Phytosterin, Picrinsäure, Pilocarpin, Pimecrolimus, Pimozid, Pinaverium Bromid, Pindolol, Pioglitazon, Pipamperon, Pipazetat, Pipecuronium Bromid, Pipemidsäure, Pipenzolat, Piperacillin, Piprinhydrinat, Piracetam, Pirarubicin, Pirbuterol, Pirenzepin, Piritramid, Piroxicam, Pivmecillinam, Pizotifen, Podophyllotoxin, Polidocanol, Polycarbophil, Polyestradiol Phosphat, Polymyxin B, Polymyxin-B, Polystyrolsulfonsäure, Porfimer, Prajmalin, Prajmal Pentaerythrityl tetranitrate, pentamidine, Pentetrazol, Inpentetreotide, pentosan polysulphate sodium, pentoxifylline, Pentoxyverine, perazine, perchloric acid, Perflenapent, Perflisopent, perflutren, pergolide, perindopril, perphenazine, phenacetin, Phenamazid, phenazone, Phenazopyridine, pheniramine, phenol, phenolphthalein, phenoxybenzamine, phenoxymethylpenicillin , phenprocoumon, phentolamine, phenylalanine, phenylbutazone, phenylephrine, phenylpropanolamine, phenyltoloxamine, phenytoin, phloroglucinol, pholedrine, phthalylsulfathiazole, physostigmine, phytomenadione, phytosterol, picric acid, pilocarpine, pimecrolimus, pimozide, pinaverium bromide, pindolol, pioglitazone, pipamperone, Pipazetat, pipecuronium bromide , pipemidic acid, Pipenzolat, piperacillin, Piprinhydrinat, piracetam, pirarubicin, pirbuterol, pirenzepine, piritramide, piroxicam, pivmecillinam, pizotifen, podophyllotoxin, polidocanol, polycarbophil, Polyestradiol phosphate, polymyxin B, polymyxin B, polystyrenesulfonic acid, porfimer, Prajmalin, Prajmal ium Bitartrat, Pramipexol, Pranoprofen, Prasteron, Pravastatin, Prazepam, Prazosin, Prednicarbat, Prednisolon, Prednison, Pregabalin, Preglumetacin, Pridinol, Prilocain, Primaquin, Primidon, Prithipendyl, Procain, Procainamid, Procarbazil, Procarbazin, Procyclidin, Progesteron, Proglumetacin, Proglumid, Proguanil, Prolin, Promethazin, Propacetamol, Propafenon, Propanolol, Propicillin, Propiverin, Propofol, Propranolol, Propylthiouracil, Propyphenazon, Protamin, Protaminsulfat, Protein C, Prothipendyl, Prothrombin, Protionamid, Protirelin, Proxymetacain, Proxyphyllin, Pseudoephedrin, Pulmonal, Pyrantel, Pyrazinamid, Pyridostigmin, Pyridostigmin Bromid, Pyridoxin, 3-Pyridylmethanol, Pyrimethamin, Pyrithion-Zink, Pyritinol, Pyrogallol, Pyrvinium, Pyrvinium Embonat, ium bitartrate, pramipexole, pranoprofen, prasterone, pravastatin, prazepam, prazosin, prednicarbate, prednisolone, prednisone, pregabalin, preglumetacin, pridinol, prilocaine, primaquine, primidone, Prithipendyl, procaine, procainamide, Procarbazil, procarbazine, procyclidine, progesterone, proglumetacin, proglumide , proguanil, proline, promethazine, propacetamol, propafenone, propranolol, propicillin, propiverine, propofol, propranolol, propylthiouracil, propyphenazone, protamine, protamine sulfate, protein C, prothipendyl, prothrombin, protionamide, protirelin, proxymetacaine, proxyphylline, pseudoephedrine, pulmonary, pyrantel, pyrazinamide, pyridostigmine, pyridostigmine bromide, pyridoxine, 3-pyridylmethanol, pyrimethamine, zinc pyrithione, pyritinol, pyrogallol, pyrvinium, pyrvinium embonate,
Quecksilberamidochlorid, Quetiapin, Quinagolid, Quinapril, Quinupristin, Quecksilberamidochlorid, quetiapine, quinagolide, quinapril, quinupristin,
Rabeprazol, Racephedrin, Raloxifen, Raltitrexed, Ramipril, Ranitidin, Rasburicase, Raubasin, Reboxetin, Repaglinid, Reproterol, Reserpin, Resorcin, Reteplase, Retinol, Reviparin, Ribavirin, Riboflavin, Rifabutin, Rifampicin, Rifamycin, Rifaximin, Rilmenidin, Riluzol, Rimexolon, Risedronsäure, Risperidon, Ritonavir, Rituximab, Rivastigmin, Rizatriptan, Rocuronium Bromid, Rofecoxib, Ropinirol, Ropivacain, Ropivacain, Rosiglitazon, Rotes Quecksilbersulfid F, Roxatidin, Roxithromycin, Rabeprazole, Racephedrin, raloxifene, raltitrexed, ramipril, ranitidine, rasburicase, raubasine, reboxetine, repaglinide, reproterol, reserpine, resorcinol, reteplase, retinol, Reviparin, ribavirin, riboflavin, rifabutin, rifampicin, rifamycin, rifaximin, rilmenidine, riluzole, rimexolone, risedronic acid, risperidone, ritonavir, rituximab, rivastigmine, rizatriptan, rocuronium bromide, rofecoxib, ropinirole, ropivacaine, ropivacaine, rosiglitazone, red mercury sulfide F, roxatidine, roxithromycin,
Salbutamol, Salicylsäure, Salmeterol, Salpetersäure, Salpetrige Säure, Salverin, Samarium [ 153 Sm] Lexidronam, Saquinavir, Schwefelhexafluorid, Scopolamin, Selegilin, Selensulfld, Serin, Sermorelin, Sertaconazol, Sertindol, Sertralin, Sevelamer, Sevofluran, Sibutramin, Silberchlorid F, Sildenafil, Silibinin, Simvastatin, Sirolimus, Solutio Formaldehydi, Somatostatin, Somatropin, Sotalol, Spagluminsäure, Spartein, Spectinomycin, Spiramycin, Spirapril, Spironolacton, Stavudin, Streptodornase, Streptokinase, Streptomycin, Strontium Ranelate, Strontiumchlorid, Strychnin, Sucralfat F, Sulbactam, Sulesomab, Sulfacetamid, Sulfadiazin, Sulfadimethoxin, Sulfaguanidin, Sulfamerazin, Sulfamethoxazol, Sulfamethoxydiazin, Sulfametrol, Sulfanilamid, Sulfasalazin, Sulfathiazol, Sulfisomidin, Sulindac, Sulodexid, Sulphur Hexafluoride, Sulpirid, Sulproston, Sultamicillin, Sultiam, Sumatriptan, Suxamethonium, Salbutamol, salicylic acid, salmeterol, nitric acid, nitrous acid, Salverin, samarium [153 Sm] lexidronam, saquinavir, sulfur hexafluoride, scopolamine, selegiline, Selensulfld, serine, Sermorelin, sertaconazole, sertindole, sertraline, sevelamer, sevoflurane, sibutramine, silver chloride F, sildenafil , silibinin, simvastatin, sirolimus, Solutio Formaldehydi, somatostatin, somatropin, sotalol, Spagluminsäure, sparteine, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptodornase, streptokinase, streptomycin, strontium ranelate, strontium chloride, strychnine, sucralfate F, sulbactam, sulesomab, sulfacetamide, sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamerazine, sulfamethoxazole, Sulfamethoxydiazin, sulfametrole, sulfanilamide, sulfasalazine, sulfathiazole, sulfisomidine, sulindac, sulodexide, Sulfur hexafluoride, sulpiride, sulprostone, sultamicillin, sulthiame, sumatriptan, suxamethonium,
Tacalcitol, Tacrolimus, Tadalafil, Tamoxifen, Tamsulosin, Tasonermin, Taurolidin, Tazaroten, Tazobactam, Tegafur, Teicoplanin, Telithromycin, Telmisartan, Temoporfin, Temozolomid, Tenecteplase, Teniposid, Tenofovir, Tenofovir Disoproxil, Tenoxicam, Terazosin, Terbinafin, Terbutalin, Terfenadin, Teriparatid, Terizidon, Terlipressin, Testosteron, Testosteronpropionat, Testosteronundecanonat, Tetracain, Tetracosactid, Tetracyclin, Tetrafluoroborat-1+, Tetrofosmin, Tetryzolin, Thallium Chlorid [ 201 TI], Theobromin, Theodrenalin, Theodrenalin, Theophyllin, Thiamazol, Thiamin, Thiethylperazin, Thiocolchicosid, Thiopental, Thiondazin, Thiotepa, Threonin, Thrombin, Thrombokinase, Thymol, Thyrotropin Alfa, Tiagabin, Tianeptin, Tiaprid, Tibolon, Ticlopidin, Tiludronsäure, Timolol, Tinzaparin, Tioconazol, Tioguanin, Tiotropium Bromid, Tirilazad, Tirofiban, Tisopurin, Tizamidin, Tizanidin, Tobramycin, Tocainid, Tolazolin, Tolbutamid, Tolcapon, Tolfenaminsäure, Tolmetin, Tolperison, Tolterodin, Tacalcitol, tacrolimus, tadalafil, tamoxifen, tamsulosin, tasonermin, taurolidine, tazarotene, tazobactam, tegafur, teicoplanin, telithromycin, telmisartan, temoporfin, temozolomide, tenecteplase, teniposide, tenofovir, tenofovir disoproxil, tenoxicam, terazosin, terbinafine, terbutaline, terfenadine, teriparatide , terizidone, terlipressin, testosterone, testosterone propionate, Testosteronundecanonat, tetracaine, tetracosactide, tetracycline, tetrafluoroborate-1 +, tetrofosmin, tetryzoline, thallium chloride [201 TI], theobromine, Theodrenalin, Theodrenalin, theophylline, thiamazole, thiamine, thiethylperazine, thiocolchicoside, thiopental , Thiondazin, thiotepa, threonine, thrombin, thrombokinase, thymol, thyrotropin alfa, tiagabine, tianeptine, tiapride, tibolone, ticlopidine, tiludronic acid, timolol, tinzaparin, tioconazole, thioguanine, tiotropium bromide, tirilazad, tirofiban, Tisopurin, Tizamidin, tizanidine, tobramycin , tocainide, Tolazolin, tolbutamide, tolcapone, tolfenamic acid, tolmetin, tolperisone, tolterodine, Topiramat, Topotecan, Torasemid, Toremifen, Tramazolin, Trandolapril, Tranexamsäure, Tranylcypromin, Trapidil, Trastuzumab, Travoprost, Trazodon, Tretinoin, Triamcinolon, Triamcinolonacetonid, Triamteren, Trichloressigsäure, Triethylperazin, Trifluoperazin, Triflupromazin, Trihexyphenidyl, Trimebutin, Trimecain, Trimegeston, Trimetazidin, Trimethoprim, Trimipramin, Tripelenamin, Triprolidin, Triptorelin, Tritoqualin, Trofosfamid, Tromantadin, Trometamol, Tropicamid, Tropisetron, Trospium, Tryptophan, Tubocurarin Chlorid, Tulobuterol, Tyloxapol, Tyrosin, Tyrothricin, Topiramate, topotecan, torasemide, toremifene, tramazoline, trandolapril, tranexamic acid, tranylcypromine, trapidil, trastuzumab, travoprost, trazodone, tretinoin, triamcinolone, triamcinolone acetonide, triamterene, trichloroacetic acid, triethylperazine, trifluoperazine, triflupromazine, trihexyphenidyl, trimebutine, trimecaine, trimegestone, trimetazidine, trimethoprim, trimipramine, tripelennamine, triprolidine, triptorelin, Tritoqualin, trofosfamide, tromantadine, trometamol, tropicamide, tropisetron, trospium, tryptophan, tubocurarine chloride, tulobuterol, tyloxapol, tyrosine, tyrothricin,
Unoproston, Urapid, Urapidil, Urokinase, Ursodeoxycholsäure, Unoprostone, uRapid, urapidil, urokinase, ursodeoxycholic acid,
Valaciclovir, Valdecoxib, Valganciclovir, Valin, Valproinsäure, Valsartan, Vancomycin, Vardenafil, Vecurmium, Vecuronium Bromid, Venlafaxin, Verapamil, Verteporfin, Vigabatrin, Viloxacin, Vinblastin, Vincamin, Vincristin, Vindesin, Vinorelbin, Vinpocetin, Viquidil, Voriconazol, Votumumab, Valaciclovir, valdecoxib, valganciclovir, valine, valproic acid, valsartan, vancomycin, vardenafil, Vecurmium, vecuronium bromide, venlafaxine, verapamil, verteporfin, vigabatrin, Viloxacin, vinblastine, vincamine, vincristine, vindesine, vinorelbine, vinpocetine, Viquidil, voriconazole, votumumab,
Wasserstoffperoxid, hydrogen peroxide,
Xantinol Nicotinat, Xipamid, Xylometazolin, Xantinol nicotinate, Xipamide, xylometazoline,
Yohimbin, Yttrium 90 Y Chlorid, Yohimbine, yttrium 90 Y chloride,
Zalcitabin, Zaleplon, Zanamivir, Zidovudin, Zinc Acetate Dihydrate, Zinkchlorid, Zinkcitrat, Zinksulfat, Ziprasidon, Zofenopril, Zoledronsäure, Zolmitriptan, Zolpidem, Zolpidemtartrat, Zopiclon, Zotepin, Zucklopantexol, und Zuclopenthixol. Zalcitabine, zaleplon, zanamivir, zidovudine, Zinc Acetate Dihydrate, zinc chloride, zinc citrate, zinc sulfate, ziprasidone, zofenopril, zoledronic acid, zolmitriptan, zolpidem, zolpidem tartrate, zopiclone, zotepine, Zucklopantexol, and zuclopenthixol. - Die vorstehend genannten Verbindungen sind vorwiegend durch ihre internationeln Freinamen (INN) benannt und dem Fachmann bekannt. The above compounds are primarily by their international ioneln name (INN) named and known in the art. Hinsichtlich weiterer Einzelheiten kann beispielsweise verwiesen werden auf International Nonproprietary Names (INN) for Pharmaceutical Substances, World Health Organisation (WHO). For further details, for example, can be made to International Nonproprietary Names (INN) for Pharmaceutical Substances, World Health Organization (WHO).
- Des weiteren kann zusätzlich zur Erzielung der notwendigen Bruchfestigkeit der erfindungsgemäßen Darreichungsform mindestens ein natürliches, halbsynthetisches oder synthetisches Wachs (D) eingesetzt werden (= Komponente (D)). Further, in addition to achieve the necessary breaking strength of the dosage form according to the invention at least one natural, semi-synthetic or synthetic wax (D) can be used (= component (D)). Bevorzugt sind Wachse mit einem Erweichungspunkt von mindestens 50°C, bevorzugter mindestens 55°C, noch bevorzugter mindestens 60°C, am bevorzugtesten mindestens 65°C und insbesondere mindestens 70°C. Preferably waxes having a softening point of at least 50 ° C, more preferably at least 55 ° C, more preferably at least 60 ° C, bevorzugtesten least 65 ° C and especially at least 70 ° C. Besonders bevorzugt sind Carnaubawachs und Bienenwachs. Particularly preferred are carnauba wax and beeswax. Ganz besonders bevorzugt ist Carnaubawachs. Most particularly preferred is carnauba wax. Carnaubawachs ist ein natürliches Wachs, das aus den Blättern der Camaubapalme gewonnen wird und einen Erweichungspunkt von wenigstens 80°C aufweist. Carnauba wax is obtained from the leaves of the Camaubapalme and has a softening point of at least 80 ° C a natural wax. Beim zusätzlichen Einsatz der Wachskomponente wird diese zusammen mit wenigstens einem Polymeren (C) in solchen Mengen eingesetzt, dass die Darreichungsform eine Bruchfestigkeit von mindestens 400 N, vorzugsweise mindestens 500 N, aufweist. When additional use of this wax component together with at least one polymer (C) is used in quantities such that the dosage form exhibits a breaking strength of at least 400 N, preferably at least 500 N,.
- Als Hilfsstoffe (B) können die üblichen für die Formulierung von festen Darreichungsformen bekannten Hilfsstoffe verwendet werden. As auxiliary substances (B) which are customary for the formulation of solid dosage forms known adjuvants can be used. Vorzugsweise sind dies Weichmacher, wie Triacetin und Polyethylenglykol, vorzugsweise ein niedermolekulares Polyethylenglykol, Hilfsstoffe, die Wirkstofffreisetzung beeinflussende, vorzugsweise hydrophobe oder hydrophile, vorzugsweise hydrophile Polymere, ganz besonders bevorzugt Hydroxypropylmethylcellulose, und/oder Antioxidantien. These are preferably plasticisers, such as triacetin and polyethylene glycol, preferably a low molecular weight polyethylene glycol, auxiliary substances which influence active ingredient release, preferably hydrophobic or hydrophilic, preferably hydrophilic polymers, very particularly preferably hydroxypropyl methylcellulose, and / or antioxidants. Vorzugsweise werden als hydrophile Matrixmaterialien Polymere, besonders bevorzugt Celluloseether, Celluloseester und/oder Acrylharze verwendet. Preferably cellulose ethers, Celluloseester and / or acrylic resins are used as hydrophilic matrix materials are polymers, especially preferably used. Ganz besonders bevorzugt werden als Matrixmaterialien Ethylcellulose, Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Hydroxymethylcellulose, Poly(meth)acrylsäure und/oder deren Derivate, wie deren Salze, Amide oder Ester eingesetzt. are very particularly preferred as matrix materials ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly (meth) acrylic acid and / or their derivatives such as their salts, amides or esters. Als Antioxidantien eignen sich Ascorbinsäure, Butylhydroxyanisol (BHA), Butylhydroxytoluol (BHT), Salze der Ascorbinsäure, Monothioglycerin, phosphorige Säure, Vitamin C, Vitamin E und dessen Derivate, Natriumbisulfit, besonders bevorzugt Butylhydroxytoluol oder Butylhydroxyanisol und α-Tocopherol. Suitable antioxidants are ascorbic acid are suitable, butylhydroxyanisole (BHA), butylated hydroxytoluene (BHT), salts of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and derivatives thereof, sodium bisulfite, particularly preferably butylhydroxytoluene or butylhydroxyanisole and α-tocopherol.
- Das Antioxidanz wird vorzugsweise in Mengen von 0,01 bis 10 Gew.%, vorzugsweise 0,03 bis 5 Gew.%, bezogen auf das Gesamtgewicht der Darreichungsform, eingesetzt. The antioxidant is preferably used in amounts of 0.01 to 10.%, Preferably 0.03 to 5 wt.%, Based on the total weight of the dosage form.
- Die erfindungsgemäßen Darreichungsformen zeichnen sich dadurch aus, dass sie aufgrund ihrer Bruchfestigkeit mit Hilfe von üblichen Zerkleinerungsmitteln, wie Mörser und Pistill, nicht zu pulverisieren sind. The preparations according to the invention are distinguished in that they can not be pulverized due to their breaking strength using conventional crushing means such as a mortar and pestle. Eine Überdosierung ist dadurch praktisch ausgeschlossen. An overdose is practically impossible. Um jedoch die Bruchfestigkeit der Darreichungsform weiter zu erhöhen, können die erfindungsgemäßen Darreichungsformen als Hilfsstoffe (B) weitere Bruchfestigkeits-erhöhende Mittel enthalten. However, to increase the breaking strength of the dosage form further dosage forms of the invention as auxiliaries (B) may contain further breaking strength enhancing agents.
- Die erfindungsgemäße Darreichungsform ist vorzugsweise fest und eignet sich zur oralen, vaginalen oder rektalen, vorzugsweise zur oralen Einnahme. The dosage form according to the invention is preferably solid and is suitable for oral, vaginal or rectal, preferably for oral administration. Vorzugsweise ist sie nicht filmförmig. it is not film form preferably. In einer weiteren bevorzugten Ausführungsform liegt die erfindungsgemäße Darreichungsform in Form einer Tablette, einer Kapsel oder in Form eines oralen osmotischen therapeutischen Systems (OROS) vor. In a further preferred embodiment the dosage form according to the invention is in the form of a tablet, a capsule or in the form of an oral osmotic therapeutic system (OROS). In einer bevorzugten Ausführungsform liegt die erfindungsgemäße Darreichungsform als Tablette vor. In a preferred embodiment the dosage form according to the invention is present as a tablet. Die erfindungsgemäße Darreichungsform kann in multipartikulärer Form, bevorzugt in Form von Mikrotabletten, Mikrokapseln, Mikropellets, Granulaten, Sphäroiden, Perlen oder Pellets, ggf. in Kapseln abgefüllt oder zu Tabletten verpresst, vorzugsweise zur oralen Verabreichung, vorliegen. The dosage form according to the invention may assume multiparticulate form, preferably, optionally filled or in the form of microtablets, microcapsules, micropellets, granules, spheroids, beads or pellets in capsules, compressed into tablets, preferably for oral administration, are present. Vorzugsweise weisen die multipartikulären Formen eine Größe bzw. Größenverteilung im Bereich von 0,1 bis 3 mm, besonders bevorzugt im Bereich von 0,5 bis 2 mm auf. Preferably, the multiparticulates have a size or size distribution in the range of 0.1 to 3 mm, particularly preferably in the range of 0.5 to 2 mm. Je nach gewünschter Darreichungsform werden ggf. auch die üblichen Hilfsstoffe (B) zur Formulierung der Darreichungsform mitverwendet. Depending on the desired dosage form, conventional auxiliary substances (B) are optionally also used for the formulation of the dosage form.
- Die erfindungsgemäße Darreichungsform kann durch unterschiedliche Verfahren hergestellt werden, die nachfolgend näher erläutert werden: The dosage form according to the invention can be prepared by different methods, which are explained in more detail below:
Das Verfahren zur Herstellung der erfindungsgemäßen Darreichungsform umfasst bevorzugt folgende Schritte: The process for preparing the dosage form according to the invention preferably comprises the steps of: - (a) Mischen der Komponente (A), ggf. (B), (C), ggf. (D); (A) mixing the component (A), optionally (B), (C), optionally (D);
- (b) ggf. Vorformen der aus Schritt (a) erhaltenen Mischung, vorzugsweise unter Wärme- und/oder Krafteinwirkung auf die aus (a) erhaltene Mischung, wobei die zugeführte Wärmemenge bevorzugt nicht dazu ausreicht, die Komponente (C) bis zu ihrem Erweichungspunkt zu erwärmen; (B) optionally preforms from step (a) obtained mixture, preferably is insufficient under heat and / or force to the obtained from (a) mixture, the amount of heat supplied preferably to the component (C) to its softening point to heat;
- (c) Härten der Mischung unter Wärme- und Krafteinwirkung, wobei die Wärmezufuhr während und/oder vor der Krafteinwirkung erfolgen kann und die zugeführte Wärmemenge dazu ausreicht, die Komponente (C) wenigstens bis zu ihrem Erweichungspunkt zu erwärmen; (C) curing the mixture under heat and force, wherein the heat supply can be done during and / or prior to the application of force and is sufficient, the amount of heat applied, the component (C) to heat at least to its softening point;
- (d) ggf. Vereinzeln der gehärteten Mischung; (D) optionally separating the hardened mixture;
- (e) ggf. Formen der Darreichungsform; (E) optionally forms of the dosage form; und and
- (f) ggf. Beschichten mit einem Filmüberzug. (F) optionally coating with a film coating.
- Die Wärme kann direkt oder mit Hilfe von Ultraschall zugeführt werden. The heat can be supplied directly or with the help of ultrasound. Die Krafteinwirkung und/oder das Formen der Darreichungsform kann beispielsweise durch Direkttablettierung oder mit Hilfe von Extrudern erfolgen. The force and / or the shapes of the dosage form can, for example by direct or by means of extruders.
- Die folgenden Verfahrensvarianten sind besonders bevorzugt: The following process variants are particularly preferred:
- Verfahrensvariante 1: Process variant 1:
- In dieser Ausführungsform wird die erfindungsgemäße Darreichungsform vorzugsweise ohne Extruder-Einsatz hergestellt, indem vorzugsweise die Komponenten (A), ggf. (B), (C) und die ggf. vorhandene Komponente (D) gemischt werden und die resultierende Mischung ggf. nach einer Granulierung zu der Darreichungsform unter vorangehender oder gleichzeitiger Wärmeeinwirkung durch Krafteinwirkung geformt wird. In this embodiment, the dosage form according to the invention is preferably produced without using an extruder, preferably by the components (A), optionally (B), (C) and the optionally present component (D) are mixed and the resulting mixture if necessary after a granulation is formed into the dosage form with preceding or simultaneous exposure to heat by force.
- Diese Erwärmung und Krafteinwirkung zur Herstellung der Darreichungsform erfolgt ohne Extruder-Einsatz. This heating and force for the production of the dosage form is done without using an extruder.
- Die Mischung der Komponenten (A), ggf. (B), (C) und ggf. (D) erfolgt in einem dem Fachmann bekannten Mischgerät. The mixture of components (A), optionally (B), (C) and optionally (D) takes place in a mixer known to the expert. Das Mischgerät kann beispielsweise ein Wälzmischer, Schüttelmischer, Schermischer oder Zwangsmischer sein. The mixer can be for example a roll mixer, shaking, shear mixer or compulsory mixer.
- Die resultierende Mischung wird vorzugsweise direkt zu der erfindungsgemäßen Darreichungsform unter vorangehender oder gleichzeitiger Wärmeeinwirkung durch Krafteinwirkung geformt. The resulting mixture is preferably molded directly to the inventive dosage form with preceding or simultaneous exposure to heat by force. Beispielsweise kann die Mischung durch Direkttablettierung zu Tabletten geformt werden. For example, the mixture may be formed by direct compression into tablets. Bei einer Direkttablettierung unter gleichzeitiger Wärmeeinwirkung wird mit Hilfe des Tablettierwerkzeugs, dh des Unterstempels, Oberstempels und der Matrize die zu verpressende Mischung zumindest bis zum Erweichungspunkt der Polymeren-Komponente (C) erhitzt und dabei verpresst. In direct the simultaneous action of heat by means of the tabletting tool, ie the bottom punch, top punch and the die, the mixture to be compressed at least to the softening point of the polymer component (C) is heated and pressed thereby. Bei einer Direkttablettierung unter vorangehender Wärmeeinwirkung wird das zu verpressende Gut unmittelbar vor der Tablettierung mindest bis zur Erweichungstemperatur der Komponete (C) erhitzt und anschließend mit Hilfe des Tablettierwerkzeugs verpresst. In direct preceding exposure to heat to be compressed material is immediately before the tableting least up to the softening temperature of the component attempts (C) is heated and then pressed by means of the tabletting tool.
- Die resultierende Mischung aus den Komponenten (A), ggf. (B), (C) und ggf. der Komponente (D) kann auch zuerst granuliert und anschließend unter vorangehender oder gleichzeitiger Wärmeeinwirkung unter Krafteinwirkung zu der erfindungsgemäßen Darreichungsform geformt werden. The resulting mixture of components (A), optionally (B), (C) and optionally the component (D) can also first be granulated and then molded with preceding or simultaneous exposure to heat under force to the inventive dosage form.
- Bei jeder Krafteinwirkung erfolgt diese solange, bis die Darreichungsform eine Bruchhärte von mindestens 400 N, vorzugsweise mindestens 500 N, erreicht hat. In each application of force, this is carried out until the dosage form has reached a breaking hardness of at least 400 N, preferably at least 500 N,.
- Die Granulierung kann durch Feuchtgranulation oder Schmelzgranulation in bekannten Granulatoren durchgeführt werden. Granulation may be performed by wet granulation or melt in known granulators.
- Jeder der erwähnten Verfahrensschritte, insbesondere die Erwärmungen und gleichzeitige oder nachfolgende Krafteinwirkung zur Herstellung der erfindungsgemäßen Darreichungsform erfolgt ohne Extruder-Einsatz. Each of the mentioned process steps, in particular the heating steps and simultaneous or subsequent application of force for the preparation of the dosage form according to the invention is carried out without using an extruder.
- Verfahrensvariante 2: Process variant 2:
- Bei dieser Verfahrensvariante wird die erfindungsgemäße Darreichungsform durch Thermoverformung mit Hilfe eines Extruders hergestellt, ohne dass dabei eine Verfärbung des Extrudates zu beobachten ist. In this process variant, the inventive dosage form is manufactured by thermoforming with the aid of an extruder, without causing discoloration of the extrudate is observed.
- Um das Ausmaß der Verfärbung durch diese Thermoformgebung zu untersuchen, wird zunächst die Färbung der Mischung der Ausgangkomponenten, aus denen die Darreichungsform besteht, ohne Zugabe einer farbgebenden Komponente, wie z. To investigate the extent of discoloration due to this thermoforming, first the color of the mixture of the starting components that make up the dosage form, without the addition of a coloring component such. B. einem Farbpigment oder einer eigengefärbten Komponente (z. B. α-Tocopherol) festgestellt. B. found a coloring pigment or an intrinsically colored component (for. Example, α-tocopherol). Diese Zusammensetzung wird dann erfindungsgemäß thermogeformt, wobei sämtliche Verfahrensschritte einschließlich der Kühlung des Extrudates unter einer Inertgasatmosphäre durchgeführt werden. This composition is then thermoformed according to the invention, wherein all process steps, including cooling of the extrudate, are performed under an inert gas atmosphere. Im Vergleich dazu wird dieselbe Zusammensetzung nach demselben Verfahren aber ohne Inertgasatmosphäre hergestellt. In comparison, the same composition by the same method, but without an inert gas atmosphere. Von der Ausgangszusammensetzung der erfindungsgemäß hergestellten Darreichungsform und der zum Vergleich hergestellten Darreichungsform wird die Färbung bestimmt. Of the starting composition and the dosage form according to the invention the dosage form prepared for comparison the color is determined. Die Bestimmung erfolgt mit Hilfe von „Munsell Book of Colour" von Munsell Colour Company Baltimore, Maryland, USA, Ausgabe 1966. Sofern die Färbung der erfindungsgemäß thermogeformten Darreichungsform eine Färbung mit der Identifikations-Nr. N 9,5/höchstens jedoch eine Färbung mit der Identifikations-Nr. 5Y 9/1 aufweist, wird die Thermoverformung als eine „ohne Verfärbung" eingestuft. The determination is made by means of "Munsell Book of Color" Munsell Color Company Baltimore, Maryland, USA, 1966 edition If the color of the invention thermoformed dosage form has a color with the identification no. N 9.5 / maximum of staining with having the identification number. 5Y 9/1, thermoforming is classed as being "without discoloration". Sofern die Darreichungsform eine Färbung mit der Identifikations-Nr. If the dosage form has a color with identification no. 5Y 9/2 oder mehr aufweist bestimmt gemäß Munsell Book of Colour wird die Thermoverformung als eine „mit Verfärbung" eingestuft. 5Y 9/2 or greater, as determined according to the Munsell Book of Color, the thermoforming is classed as a "with discoloration".
- Überraschenderweise weisen die erfindungsgemäßen Darreichungsformen keine gemäß der vorstehenden Klassifizierung einzustufende Verfärbung auf, wenn das gesamte Herstellungsverfahren unter einer Inertgasatmosphäre, vorzugsweise unter einer Stickstoffatmosphäre mit Hilfe eines Extruders zur Thermoformgebung durchgeführt wird. Surprisingly, dosage forms of the invention have not be classified according to the above classification discoloration, if the entire manufacturing process is carried out under an inert gas atmosphere, preferably under a nitrogen atmosphere using an extruder for thermoforming.
- Diese erfindungsgemäße Variante zur Herstellung der erfindungsgemäßen Darreichungsformen ist gekennzeichnet dadurch, dass man This variant of the invention for the preparation of the dosage forms according to the invention is characterized in that one
- z) die Komponenten (A), ggf. (B), (C) und die gegebenenfalls vorhandene Komponente (D) mischt, z) components (A), optionally (B), (C) and the optionally present component (D) are mixed,
- y) die resultierende Mischung im Extruder mindestens bis zum Erweichungspunkt der Komponente (C) erwärmt und unter Krafteinwirkung durch die Austrittsöffnung des Extruders extrudiert, y) the resultant mixture in the extruder at least up to the softening point of component heated (C) and extruded under force through the outlet opening of the extruder,
- x) das noch plastische Extrudat vereinzelt und zur Darreichungsform formt oder x) forms the still plastic extrudate is singulated and dosage form
- w) das abgekühlte und ggf. wieder erwärmte vereinzelte Extrudat zur Darreichungsform formt, f) shaping the cooled and optionally reheated singulated extrudate into the dosage form,
- Das Mischen der Komponenten gemäß dem Verfahrensschritt z) kann ebenfalls bereits in dem Extruder erfolgen. The mixing of the components according to process step z) may also proceed in the extruder.
- Die Mischung der Komponenten (A), ggf. (B), (C) und ggf. (D) kann auch in einem dem Fachmann bekannten Mischgerät erfolgen. The mixture of components (A), optionally (B), (C) and optionally (D) may also take place in a well-known to those skilled mixer. Das Mischgerät kann beispielsweise ein Wälzmischer, Schüttelmischer, Schermischer oder Zwangsmischer sein. The mixer can be for example a roll mixer, shaking, shear mixer or compulsory mixer.
- Vorzugsweise wird vor dem Abmischen mit den weiteren Komponenten die Komponente (C) und die gegebenenfalls vorhandene Komponente (D) erfindungsgemäß mit einem Antioxidanz versehen. Preferably prior to the mixing with the other components, the component (C) and the optionally present component (D) according to the invention provided with an antioxidant. Dies kann durch Vermischen der beiden Komponenten (C) und dem Antioxidanz erfolgen, vorzugsweise indem das Antioxidanz in einem leicht flüchtigen Lösungsmittel aufgelöst oder suspendiert und diese Lösung oder Suspension mit der Komponente (C) und der gegebenenfalls vorhandenen Komponente (D) homogen vermischt und das Lösungsmittel durch Trocknung, vorzugsweise unter Inertgasatmosphäre, entfernt wird. This may be by mixing the two components (C) and carried to the antioxidant, preferably by the antioxidant dissolved or suspended in a volatile solvent, and this solution or suspension with component (C) and the optionally present component (D) were homogeneously mixed, and the solvent is removed by drying, preferably under inert gas atmosphere.
- Die im Extruder bis mindestens zum Erweichungspunkt der Komponente (C) erwärmte, vorzugsweise schmelzflüssige Mischung aus dem Extruder wird durch eine Düse mit mindestens einer Bohrung extrudiert. The heated in the extruder at least up to the softening point of component (C), preferably molten mixture from the extruder is extruded through a die with at least one bore.
- Vorzugsweise werden zur Durchführung des erfindungsgemäßen Verfahrens übliche Extruder, besonders bevorzugt Schneckenextruder, die sowohl mit einer oder mit zwei Schnecken ausgerüstet sind, eingesetzt. Preferably be used for implementing the method according to the invention conventional extruders, particularly preferably screw extruders which are equipped both with one or two screws.
- Vorzugsweise weist der Extruder mindestens zwei Temperaturzonen auf, wobei in der ersten Zone, die sich an eine Einzugs- und ggf. Mischzone anschließt, das Aufheizen der Mischung bis mindestens zum Erweichungspunkt der Komponente (C) stattfindet. Preferably, the extruder has at least two temperature zones, which takes place in the first zone, which is adjacent to a feed and mixing zone, if necessary, heating the mixture to at least the softening point of component (C). Der Durchsatz der Mischung liegt vorzugsweise bei 2,0 kg bis 8,0 kg/Stunde. The throughput of the mixture is preferably from 2.0 kg to 8.0 kg / hour.
- Nach Erwärmung bis mindestens zum Erweichungspunkt der Komponente (C) wird die aufgeschmolzene Mischung mit Hilfe der Schnecken gefördert, weiter homogenisiert, komprimiert bzw. kompaktiert, so dass sie unmittelbar vor dem Austritt aus der Extruderdüse einen Mindestdruck von 5 bar, vorzugsweise mindestens 10 bar aufweist, und durch die Düse als Extrusionsstrang oder Extrusionsstränge, je nachdem wie viele Bohrungen die Düse aufweist, extrudiert. After heating to at least the softening point of component (C), the molten mixture is conveyed with the aid of the screws, further homogenised, compressed or compacted such that, immediately before emerging from the extruder die a minimum pressure of 5 bar, preferably at least 10 bar comprising , and extruded through the die as an extruded strand or strands, depending on how many holes having the nozzle. Die Düsengeometrie bzw. die Geometrie der Bohrungen ist frei wählbar. The die geometry or the geometry of the bores is freely selectable. So kann die Düse bzw. die Bohrungen einen runden, oblongen oder ovalen Querschnitt aufweisen, wobei der runde Querschnitt vorzugsweise einen Durchmesser von 0,1 mm bis 15 mm, der oblonge Querschnitt vorzugsweise mit einer maximalen Längsanpassung von 21 mm und einer Querausdehnung von 10 mm vorliegt. Thus, the die or the bores may have a round, oblong or oval cross section, wherein the round cross-section preferably has a diameter of 0.1 mm to 15 mm and the oblong cross-section preferably has a maximum lengthwise extension of 21 mm and a crosswise extension of 10 mm is present. Vorzugsweise hat die Düse bzw. die Bohrungen einen runden Querschnitt. Preferably, the die or the bores have a round cross section. Der Mantel des erfindungsgemäß zum Einsatz kommenden Extruders kann beheizt oder gekühlt werden. The jacket of the invention used according to the extruder can be heated or cooled. Die entsprechende Temperierung, dh Beheizung oder Kühlung, richtet sich danach, dass die zu extrudierende Mischung mindestens eine Durchschnittstemperatur (Produkttemperatur) entsprechend der Erweichungstemperatur der Komponente (C) aufweist und nicht über eine Temperatur steigt, bei welcher die zur verarbeitende physiologisch wirksame Substanz (A) Schaden nehmen kann. The corresponding temperature control, ie heating or cooling, is so arranged, comprises that the mixture to be extruded at least an average temperature (product temperature) corresponding to the softening point of component (C) and does not rise above a temperature at which the physiologically active for processing the substance (A can take) damage. Vorzugsweise wird die Temperatur der zu extrudierenden Mischung unter 180°C, vorzugsweise unter 150°C, aber mindestens auf die Erweichungstemperatur der Komponente (C), eingestellt. Preferably, the temperature of the mixture to be extruded below 180 ° C, preferably (C) is set below 150 ° C, but at least to the softening temperature of the component.
- Nach der Extrusion der geschmolzenen Mischung und gegebenenfalls Kühlung des extrudierten Stranges bzw. der extrudierten Stränge erfolgt vorzugsweise eine Zerkleinerung der Extrudate. After extrusion of the molten mixture and optional cooling of the extruded strand or extruded strands comminution of the extrudate preferably takes place. Diese Zerkleinerung kann vorzugsweise durch Zerschneiden der Extrudate mittels mitlaufender oder rotierender Messer, Wasserstrahlschneider, Drähten, Klingen oder mit Hilfe von Laserschneidern durchgeführt werden. This comminution can be preferably carried out by cutting up the extrudates by means of revolving or rotating knives, water jet cutters, wires, blades or with the aid of laser cutters.
- Für eine Zwischenlagerung bzw. Endlagerung des ggf. vereinzelten Extrudates bzw. der Endform der erfindungsgemäßen Darreichungsform ist keine Inertgasatmosphäre notwendig. For intermediate storage and disposal of possibly occasional extrudate or the final shape of the dosage form, no inert gas atmosphere is necessary.
- Das vereinzelte Extrudat kann mit üblichen Methoden pelletisiert oder zu Tabletten verpresst werden, um der Darreichungsform die Endform zu geben. The singulated extrudate may be pelletized by conventional methods or pressed into tablets to give the dosage form the final shape. Es ist aber auch möglich, das strangförmige Extrudat nicht zu vereinzeln und mit Hilfe von gegenläufigen Kalanderwalzen, die auf ihren Umlaufmantel gegenüberliegende Vertiefungen aufweisen, zur Endform, vorzugsweise zu einer Tablette, zu formen und diese mit Hilfe üblicher Methoden zu vereinzeln. However, it is also possible not to singulate the extruded strands and, with the assistance of contrarotating calender rolls comprising in their outer shell opposed indentations, into the final form, preferably, to be formed into a tablet, and to singulate these by conventional methods.
- Sollte das gegebenenfalls vereinzelte Extrudat nicht sofort zur Endform geformt, sondern zur Lagerung abgekühlt werden, so ist nach der Lagerung für eine Inertgasatmosphäre, vorzugsweise für eine Stickstoffatmosphäre zu sorgen, die bei einem Erwärmen des gelagerten Extrudats bis zur Plastifizierung und endgültigen Formgebung zur Darreichungsform eingehalten werden muss. Should this not be immediately formed into the final shape, but cooled for storing optionally singulated extrudate, then after storage for an inert gas, preferably to provide a nitrogen atmosphere, which are observed during a heating of the stored extrudate up to the plasticizing and final shaping to the dosage form got to.
- Die Krafteinwirkung im Extruder auf die zumindest plastifizierte Mischung wird durch Steuerung der Umdrehungsgeschwindigkeit der Fördereinrichtung im Extruder und deren Geometrie und durch die Dimensionierung der Austrittsöffnung so eingestellt, dass sich im Extruder vorzugsweise vor der unmittelbaren Extrudierung der plastifizierten Mischung der dafür notwendige Druck aufbaut. The force in the extruder onto the at least plasticized mixture is adjusted by controlling the rotational speed of the conveying device in the extruder and the geometry and the dimensioning of the exit opening so that preferably builds up in the extruder before the direct extrusion of the plasticized mixture of the requisite pressure. Durch einfache Vorversuche können für die jeweilige Zusammensetzung die notwendigen Extrusionsparameter festgestellt werden, die zu einer Darreichungsform mit einer Bruchfestigkeit von mindestens 400 N, vorzugsweise mindestens 500 N führen. By simple preliminary tests the necessary extrusion parameters can be determined for each composition, which result in a dosage form with a breaking strength of at least 400 N, preferably at least 500 N.
- Verfahrensvariante 3: Process variant 3:
- Bei dieser Verfahrensvariante zur Herstellung der erfindungsgemäßen Darreichungsform wird zunächst eine homogene Mischung aus wenigstens der Komponente (A) und der Komponente (C) (= Bindemittel) hergestellt. In this process variant for the preparation of the dosage form according to the invention a homogeneous mixture of at least the component (A) and the component (C) (= binder) is first prepared. Dieser Mischung können noch weitere Hilfsstoffe, wie zum Beispiel Füllstoffe, Weichmacher, Gleitmittel oder Farbstoffe, zugemischt werden. This mixture may also contain other additives such as fillers, plasticizers, lubricants or dyes are added. Vorzugsweise wird als Weichmacher ein niedermolekulares Polyethylenglykol verwendet. Preferably, a low molecular weight polyethylene glycol is used as a plasticizer.
- Das Mischen kann mit Hilfe von üblichen Mischern durchgeführt werden. The mixing can be carried out using conventional mixers. Beispielsweise sind als Mischer Wälzmischer, die auch als Fall-, Trommel- oder Rotationsmischer bekannt sind, Containermischer, Fassmischer (Rhönradmischer oder Taumelmischer) oder Schüttelmischer, Schermischer, Zwangsmischer, Pflugscharmischer, Planeten-Mischkneter, Z-Kneter, Sigma-Kneter, Fluidmischer oder Intensivmischer geeignet. For example, mixers are roll mixers, which are also known as tumbler, drum or rotary mixers, container mixers, barrel mixers (drum hoop mixers or tumbling mixers) or shaking mixers, shear mixers, compulsory mixers, plow blade mixers, planetary kneader, Z kneaders, sigma kneaders, fluid mixers or intensive mixer suitable.
- Die Auswahl des geeigneten Mischers hängt unter anderem von der Rieselfähigkeit und Kohäsionskräfte des Mischgutes ab. The selection of the suitable mixer depends among other things on the viscosity and cohesiveness of the mix.
- Die Mischung wird anschließend einer Formgebung unterworfen. The mixture is then subjected to shaping. Vorzugsweise während oder nach der Ultraschalleinwirkung erfolgt die Formgebung der Mischung, vorzugsweise durch Kompaktierung. Preferably during or after the ultrasonic action, the shaping of the mixture takes place, preferably by compaction.
- Bei der Ultraschalleinwirkung ist es besonders bevorzugt, dass ein direkter Kontakt zwischen der Mischung und der Sonotrode des Ultraschallgerätes vorhanden ist. In the ultrasonic action, it is particularly preferred that a direct contact between the mixture and the sonotrode of the ultrasound device is present. Vorzugsweise wird gemäß dem erfindungsgemäßen Verfahren ein Ultraschallgerät eingesetzt, wie es in Preferably according to the inventive method, an ultrasonic device is used as shown in
1 1 dargestellt ist. is shown. - In dieser In this
1 1 bedeutet ( means (1 1 ) die Presse, mit der die notwendige Kraft aufgebracht wird, ( ) The press with which the necessary force is applied, (2 2 ) den Konverter, ( ) The converter (3 3 ) den Booster, ( ) The booster, (4 4 ) die Sonotrode, ( ) The sonotrode, (5 5 ) die Matrize zur Formgebung, ( ), The die for molding (6 6 ) den Unterstempel, ( ) The bottom punch, (7 7 ) die Grundplatte, ( ) The base plate (8 8th ) und ( ) and (9 9 ) den Ultraschallgenerator und die Steuerung des Gerätes. ) The ultrasound generator and the control of the device. Die verwendeten Bezugszeichen beziehen sich ausschließlich auf The reference numerals used relate solely to1 1 . , - Bei der Ultraschalleinwirkung sollte eine Frequenz von 1 kHz bis 2 MHz, vorzugsweise 15 bis 40 kHz, eingehalten werden. In the ultrasonic action, a frequency of 1 kHz to 2 MHz should preferably be 15 to 40 kHz are respected. Die Dauer der Ultraschalleinwirkung sollte solange erfolgen, bis eine Erweichung des Polymers (C) erreicht wird. The duration of the ultrasonic action should be performed until softening of the polymer (C) is achieved. Vorzugsweise wird dies innerhalb von wenigen Sekunden, besonders bevorzugt innerhalb von 0,1 bis 5 Sekunden, vorzugsweise 0,5 bis 3 Sekunden, erreicht. Preferably, this is within a few seconds, particularly preferably within 0.1 to 5 seconds, preferably reaches 0.5 to 3 seconds.
- Durch die Ultraschalleinwirkung und die Krafteinwirkung erfolgt eine uniforme Energieübertragung, wodurch ein schnelles und homogenes Sintern der Mischung erreicht wird. By ultrasonic action and the force ensure uniform energy transfer, whereby a rapid and homogeneous sintering of the mixture takes place is achieved. Dadurch werden Darreichungsformen erhalten, die eine Bruchfestigkeit von mindestens 400 N, vorzugsweise mindestens 500 N haben und damit nicht pulverisierbar sind. This dosage forms are obtained which have a breaking strength of at least 400 N, preferably at least 500 N and thus are not to pulverization.
- Bevor die Formgebung durchgeführt wird, kann nach dem Mischvorgang eine Granulierung der Mischung erfolgen, wonach die daraus resultierenden Granulate unter Ultraschalleinwirkung und Krafteinwirkung zu der Darreichungsform, wie Tabletten, geformt werden. Before shaping is performed, a granulation can be carried out of the mixture, after which the resulting granules are molded under the action of ultrasound and force to the dosage form such as tablets after the mixing process.
- Die Granulierung kann in den dem Fachmann bekannten Maschinen und Apparaturen durchgeführt werden. The granulation can be carried out in known in the art machinery and equipment.
- Sofern die Granulierung als Feuchtgranulierung durchgeführt wird, können als Granulierflüssigkeit Wasser oder wässrige Lösungen, wie zB Ethanol/Wasser oder Isopropanol/Wasser, eingesetzt werden. Provided that the granulation is carried out as wet granulation, granulation can be used as water or aqueous solutions, such as ethanol / water or isopropanol / water, may be used.
- Die Mischung oder die daraus hergestellten Granulate können auch zur weiteren Formgebung einer Schmelzextrusion unterworfen werden, wobei die Mischung unter Ultraschalleinwirkung und Krafteinwirkung zum Schmelzen gebracht wird und durch Düsen anschließend extrudiert wird. The mixture or the granules produced therefrom may also be subjected to further shaping a melt-extrusion, wherein the mixture is caused to melt under the action of ultrasound and force and is then extruded through nozzles. Die so gewonnenen Stränge oder der so gewonnene Strang kann mit Hilfe von bekannten Vorrichtungen auf die gewünschte Länge vereinzelt werden. The thus obtained strands or strand obtained in this way can be isolated with the aid of known devices to the desired length. Die so vereinzelten Formlinge können weiterhin gegebenenfalls unter Ultraschalleinwirkung und Krafteinwirkung zu der Endform verarbeitet werden. The thus isolated moldings can be processed with ultrasonication and application of force to the final form further optionally.
- Die Endformgebung zu der Darreichungsform erfolgt vorzugsweise unter Kraftanwendung in entsprechenden Formen. The final shaping to the dosage form preferably takes place under application of force in appropriate molds.
- Die vorstehend beschriebenen Formlinge können auch gemäß einem Kalandrierverfahren hergestellt werden, indem die Mischung bzw. die daraus hergestellten Granulate zunächst mittels Ultraschall- und Krafteinwirkung plastifiziert und durch eine entsprechende Düse extrudiert werden. The blanks described above can also be prepared according to a calendering process by passing the mixture or the granules produced therefrom by means of ultrasonic and plasticized first force and be extruded through a corresponding nozzle. Diese Extrudate werden anschließend zwischen zwei gegenläufig rotierenden Formwalzen zur endgültigen Form geformt, vorzugsweise unter Krafteinwirkung. These extrudates are then shaped between two counter-rotating molding rolls to the final form, preferably under force.
- Wie bereits erwähnt, erfolgt die Formgebung zu der Endform der Darreichungsform durch Einsatz einer Mischung umfassend die Substanz (A) und das Polymer (C) mit einer Bruchfestigkeit von mindestens 400 N, vorzugsweise mindestens 500 N, vorzugsweise in Pulverform durch direkte Komprimierung unter Krafteinwirkung, wobei auf diese Mischung vor oder während der Krafteinwirkung Ultraschalleinwirkung vorgesehen ist. As already mentioned, shaping to yield the final shape of the dosage form by use of a mixture comprising the substance (A) and the polymer (C) having a breaking strength of at least 400 N, preferably at least 500 N, preferably in powder form by direct compression with application of force wherein, prior to this mixing or during the force effect of ultrasound is provided. Die Kraft ist maximal die Kraft, die man üblicherweise zur Formgebung von Darreichungsformen, wie Tabletten, verwendet bzw. zum Verpressen von Granulaten zu der entsprechenden Endform. The force is a maximum of the force that is commonly used for shaping of dosage forms such as tablets or granules for pressing to the corresponding final shape.
- Die erfindungsgemäß hergestellten Tabletten können auch Mehrschichttabletten sein. The tablets according to the invention may also be multilayer tablets.
- Bei Mehrschichttabletten ist wenigstens die Schicht, welche die Substanz (A) enthält, einer Ultraschalleinwirkung und Krafteinwirkung zu unterziehen. In multilayer tablets, at least the layer containing the substance (A), an ultrasonic action, and the action of force is to be subjected.
- Die entsprechende notwendige Krafteinwirkung kann auch mit Hilfe von Extruderwalzen oder von Kalendarwalzen auf die Mischung aufgebracht werden. The corresponding necessary application of force may be applied to the mixture with the aid of extruder rolls or calender rolls. Vorzugsweise erfolgt die Formgebung der Darreichungsformen durch direktes Verpressen einer pulverförmigen Mischung aus den Komponenten der Darreichungsform oder entsprechenden daraus gebildeten Granulaten, wobei vorzugsweise während oder vor der Formgebung die Ultraschalleinwirkung erfolgt. Preferably, the shape of the dosage forms by direct compression of a powdered mixture of the components of the dosage form or corresponding granules formed therefrom, whereby preferably during or before shaping the ultrasonic action takes place. Diese Einwirkung erfolgt solange, bis das Polymer (C) erweicht ist, was üblicherweise in weniger als 1 Sekunde bis maximal 5 Sekunden erreicht wird. This action continues until the polymer is softened (C), which is typically achieved in less than 1 second to at most 5 seconds.
- Verfahrensvariante 4: Process variant 4:
- Bei dieser Verfahrensvariante zur Herstellung der erfindungsgemäßen Darreichungsform werden die Komponenten (A), (C) und ggf. (D) und ggf. vorhandene Hilfsstoffe (B), wie Antioxidantien, Weichmacher und/oder retardierende Hilfsstoffe mit Hilfe eines Planetwalzen-Extruders zu der erfindungsgemäßen Darreichungsform verarbeitet. In this process variant for the preparation of the dosage form according to the invention, the components (A), (C) and optionally (D) and optionally present auxiliary substances (B), such as antioxidants, plasticizers and / or delayed-release auxiliary substances with the help of a planetary roller extruder, to the inventive dosage form processed.
- Planetwalzen-Extruder sind bekannt und ua ausführlich im Handbuch der Kunststoff-Extrusionstechnik 1 (1989) „Grundlagen" im Kapitel 1.2 „Klassifizierung von Extrudern" Seiten 4 bis 6 beschrieben. Planetary roller extruders are known and are, inter alia, in detail in the Handbook of Plastics Extrusion Technology 1 (1989) "Foundations" in section 1.2 "Classification of extruders" pages 4 to. 6 Die entsprechende Beschreibung wird hiermit als Referenz eingeführt und gilt als Teil der Offenbarung. The corresponding description is hereby introduced as a reference and is deemed part of the disclosure.
- Im folgenden wird der Einsatz eines Planetwalzen-Extruders in dem erfindungsgemäßen Verfahren anhand der In the following, the use of a planetary roller extruder in the inventive method is based on the
2 2 und and3 3 erläutert. explained. Diese Erläuterungen sind lediglich beispielhaft und schränken den allgemeinen Erfindungsgedanken nicht ein. These explanations are merely exemplary and do not restrict the general inventive idea. -
2 2 zeigt den Schnitt durch einen Planetwalzen-Extruder und shows the section of a planetary roller extruder and -
3 3 zeigt die Wirkungsweise des Planetwalzen-Extruders. shows the operation of the planetary roller extruder. - In In
2 2 ist ein Planetwalzen-Extruder dargestellt, der gemäß dem erfindungsgemäßen Verfahren eingesetzt werden kann. a planetary roller extruder is shown, which can be used according to the invention. Dieser Extruder weist im wesentlichen eine Welle This extruder essentially comprises a shaft1 1 auf, die bezogen auf die Transportrichtung der zu extrudierenden Mischung der vorstehend aufgeführten Komponenten zunächst als Einzugsschnecke , which with respect to the transport direction of the mixture to be extruded of the components listed above first as auger5 5 und im weiteren als Zentralspindel and subsequently as the central spindle3 3 des Planetwalzen-Extruders gestaltet ist. of the planetary roller extruder is designed. Um die Zentralspindel Around the central spindle3 3 sind vorzugsweise drei bis sieben Planetspindeln preferably three to seven planetary spindles4 4 angeordnet, die wiederum von einem Mantel in Form eines Gehäuses arranged, in turn, by a casing in the form of a housing6 6 umgeben sind. are surrounded. - Im Planetwalzen-Extruder wird unter Bezugnahme auf In the planetary roller extruder is described with reference to
2 2 die Extrusion der im erfindungsgemäßen Verfahren zum Einsatz kommenden Zusammensetzung zur Herstellung einer pharmazeutischen Darreichungsform, vorzugsweise wie folgt durchgeführt. the extrusion of the next process of the invention for use composition for the preparation of a pharmaceutical dosage form, preferably carried out as follows. Wie durch Pfeil As indicated by arrow2 2 dargestellt, werden die zu extrudierenden Komponenten durch die Dosiereinheit shown, the components are to be extruded through the dispensing unit7 7 in dem Bereich der Einzugsschnecke in the region of the auger5 5 dosiert und durch deren Drehung (Antrieb nicht dargestellt) in Richtung der Zentralspindel and metered (not shown drive) by rotating in the direction of the central spindle3 3 befördert. promoted. Der Fachmann versteht, dass im Bereich der Einzugsschnecke ein Vermischen der Ausgangsstoffe (Komponenten) möglich ist. The skilled artisan understands that in the region of the auger mixing of the starting materials (components) is possible. Es ist aber auch möglich, die Komponenten der Darreichungsform vorzumischen und diese Mischung über die Dosiereinheit but it is also possible to pre-mix the components of the dosage form and this mixture via the metering unit7 7 in dem Bereich der Einzugsschnecke in the region of the auger5 5 zu dosieren. to dose. Im Einzugsbereich des Planetwalzen-Extruders wird die Mischung gefördert. In the catchment area of the planetary-gear extruder, the mixture is promoted. Durch Erwärmung bis mindestens zum Erweichungspunkt der Komponente (C) wird die Mischung aufgeschmolzen und dort im Bereich der Zentralspindel, dh im Extrusionsbereich die aufgeschmolzene Mischung durch Zusammenwirkung der Zentralspindel By heating to at least the softening point of component (C) is melted and the mixture there in the region of the central spindle, that is, in the extrusion area, the molten mixture by cooperation of the central spindle3 3 und der Planetspindeln and the planetary spindles4 4 gefördert, weiter homogenisiert, komprimiert bzw. kompaktiert und durch die Düse promoted further homogenised, compressed or compacted and through the nozzle8 8th als Extrusionsstrang oder Extrusionsstränge, je nachdem wie viele Bohrungen die Düse aufweist, extrudiert. as extruded strand or strands, depending on how many holes having the nozzle, extruded. Die Düsengeometrie bzw. die Geometrie der Bohrungen ist frei wählbar. The die geometry or the geometry of the bores is freely selectable. So kann die Düse bzw. die Bohrungen einen runden, oblongen oder ovalen Querschnitt aufweisen, wobei der runde Querschnitt vorzugsweise einen Durchmesser 0,1 mm bis 15 mm, der oblonge Querschnitt vorzugsweise mit einer maximalen Längsausdehnung von 21 mm und einer Querausdehnung von 10 mm vorliegt. Thus, the die or the bores may have a round, oblong or oval cross section, wherein the round cross-section preferably having a diameter from 0.1 mm to 15 mm and the oblong cross-section is preferably present with a maximum longitudinal extension of 21 mm and a crosswise extension of 10 mm , Die Extrusionsdüse kann auch als Schlitzdüse gestaltet sein. The extrusion die may also be designed as a slot. Vorzugsweise hat die Düse bzw. die Bohrungen einen runden, ovalen oder oblongen Querschnitt. Preferably, the die or the bores have a round, oval or oblong cross-section. Sowohl der Mantel Both the jacket6 6 des erfindungsgemäß zum Einsatz kommenden Planetwalzen-Extruders als auch die Zentralspindel können beheizt oder gekühlt werden. of the invention employed in accordance with planetary-gear extruder and the central spindle can be heated or cooled. Die entsprechende Temperierung, dh Beheizung oder Kühlung, richtet sich danach, dass die zu extrudierende Mischung mindestens eine Durchschnittstemperatur entsprechend der Erweichungstemperatur der Komponente (C) aufweist und nicht über eine Temperatur steigt, bei der die zur verarbeitende Substanz (A) Schaden nehmen kann. The corresponding temperature control, ie heating or cooling, depends on that the mixture to be extruded comprises at least an average temperature corresponding to the softening point of component (C) and does not rise above a temperature at which the to be processed substance (A) may be damaged. Vorzugsweise wird die Temperatur der zu extrudierenden Mischung unter 180°C, vorzugsweise unter 150°C, aber mindestens auf die Erweichungstemperatur der Komponente (C), eingestellt. Preferably, the temperature of the mixture to be extruded below 180 ° C, preferably (C) is set below 150 ° C, but at least to the softening temperature of the component. Die verwendeten Bezugszeichen beziehen sich ausschließlich auf The reference numerals used relate solely to2 2 und and3 3 . , - Nach der Extrusion der geschmolzenen Mischung und gegebenenfalls Kühlung des extrudierten Stranges bzw. der extrudierten Stränge erfolgt eine nicht in After extrusion of the molten mixture and optional cooling of the extruded strand or extruded strands is effected in a non-
2 2 dargestellte Zerkleinerung der Extrudate. Crushing the extrudates shown. Diese Zerkleinerung kann vorzugsweise durch Zerschneiden der Extrudate mittels mitlaufender oder rotierender Messer, Wasserstrahlschneider, Drähten, Klingen oder mit Hilfe von Laserschneidern durchgeführt werden. This comminution can be preferably carried out by cutting up the extrudates by means of revolving or rotating knives, water jet cutters, wires, blades or with the aid of laser cutters. - Gegebenenfalls nach einem weiteren Abkühlen der zerkleinerten Extrudate, die vorzugsweise in Scheiben vorliegen, erfolgt gegebenenfalls ein Umformen in die Endform der Darreichungsform, wobei wenn nötig, wieder Wärmeeinwirkung erfolgt. If necessary, after further cooling of the crushed extrudates, which are preferably present in slices, is optionally carried out a forming into the final shape of the dosage form, wherein, if necessary, again the influence of heat takes place.
- Diese Formgebung beispielsweise zu Tabletten kann dadurch erfolgen, dass das plastische Extrudat mit Hilfe von zwei gegenläufig angetriebenen Walzen mit vorzugsweise zur Plastifizierung einander gegenüberliegenden Vertiefungen im Walzenmantel, deren Ausführung die Tablettenform bestimmt, unter Verpressung geformt wird. This shaping into tablets, for example may take place in that the plastic extrudate by means of two counter-rotating rolls having preferably for plasticizing opposed recesses in the roller shell, the execution of which determines the form of tablets, is molded under compression.
- Es ist aber auch möglich, aus den vereinzelten Extrudaten die Tabletten jeweils mit Hilfe einer gegebenenfalls beheizten Matrize und mindestens einem formgebenden Stempel zu formen. It is also possible to form from the singulated extrudates tablet each by means of an optionally heated mold and at least one forming punch. Dazu können vorzugsweise die nach der Zerkleinerung des extrudierten Stranges erhaltenen zylinderförmigen Granulate verwendet werden. For this, the obtained after the crushing of the extruded strand cylindrical granules can be preferably used. Außer zu Tabletten verpresst, können diese Granulate oder andere erhaltene multipartikuläre Formen, wie Pellets oder Spheriode, auch in Kapseln abgefüllt werden, um als erfindungsgemäß hergestellte Darreichungsform verwendet zu werden. Except compressed into tablets, these granules obtained or other multiparticulate forms such as pellets or spheroids, can also be filled into capsules to be used as a dosage form manufactured according to the invention.
- In einer weiteren bevorzugten Ausführungsform können die durch mehrere Bohrungen der Extrusionsdüse extrudierten Stränge gegebenenfalls nach deren Abkühlung durch Verflechtung oder Umschlingung entsprechend einer Seilherstellung zu einem gegenüber den einzelnen extrudierten Strängen dickeren Strang zusammengeführt werden. In a further preferred embodiment, the extruded through a plurality of holes in the extrusion lines can be merged according to a rope production, in comparison with the individual extruded strands thicker strand optionally after cooling thereof by braiding or wrapping around. Dieser Strang kann gegebenenfalls durch Anlösen mit geeignetem Lösungsmittel oder durch Erwärmung bis zum Erweichungspunkt des Polymers (C) und gegebenenfalls Entfernen des Lösungsmittels entsprechend der vorstehend aufgeführten Zerkleinerung und Verformung eines einzelnen Stranges weiter verarbeitet werden. This strand may optionally be further processed in accordance with the above-mentioned crushing and deformation of a single strand by dissolving with a suitable solvent or by heating to the softening point of the polymer (C) and optionally removing the solvent.
-
3 3 zeigt eine Querschnitt durch den Planetwalzen-Extruder. shows a cross section through the planetary roller extruder. Um die sich drehende Zentralspindel To the rotating central spindle3 3 sind mindestens drei, in dem gezeigten Fall are at least three, in the case shown,6 6 , Planetspindeln , Planetary spindles4 4 angeordnet, deren Flanken arranged, the flanks41 41 zu einem mit dem Flanken a with the edges31 31 der Zentralspindel the central spindle4 4 und zum anderen mit den Flanken and on the other with the edges61 61 des Mantels of the shell6 6 des Planetwalzen-Extruders zusammenwirken. interaction of the planetary roller extruder. Durch die Drehung der Zentralspindel By the rotation of the central spindle3 3 und das Abrollen der jeweiligen Flanken aufeinander drehen sich die Planetspindeln and the unrolling of the respective edges to each other to rotate the planetary spindles4 4 jeweils wie mit Pfeil each as with arrow42 42 um ihre eigene Achse und wie Pfeil around its own axis and how Arrow43 43 verdeutlicht, um die Zentralspindel clarified to the central spindle4 4 herum. around. Dadurch wird die erfindungsgemäß angestrebte Komprimierung bzw. Kompaktierung der erfindungsgemäß zum Einsatz kommenden Komponentenmischung der erfindungsgemäß hergestellten Darreichungsformen bewirkt. Characterized according to the invention desired compression or compaction of the invention used according to component mixture of the dosage forms according to the invention is effected. Die verwendeten Bezugszeichen beziehen sich ausschließlich auf The reference numerals used relate solely to2 2 und and3 3 . , - Sofern notwendig, kann der zum Einsatz kommende Planetwalzen-Extruder nicht nur einen Extrusionsbereich aufweisen, sondern mindestens noch einen weiteren, um gegebenenfalls auch die zu extrudierende Mischung entgasen zu können. If necessary, the upcoming used planetary roller extruder may have not only an extrusion area, but also at least one further, to optionally degas the mixture to be extruded.
- Das erfindungsgemäße Verfahren kann diskontinuierlich oder kontinuierlich, vorzugsweise kontinuierlich, durchgeführt werden. The inventive method can be carried out batchwise or continuously, preferably continuously carried out.
- Verfahrensvariante 5: Process variant 5:
- Zur Durchführung dieser Variante zur Herstellung der erfindungsgemäßen Darreichungsform werden wenigstens die Komponenten (A), (C) und ggf. (D) und ggf. vorhandene Hilfsstoffe (B), wie Antioxidantien, Weichmacher und/oder retardierende Hilfsstoffe unter Zugabe eines Lösungsmittels für die Komponente (C), dh für das oder die Polymere (C), zu der Darreichungsform verarbeitet. To carry out this variant for the preparation of the dosage form according to the invention, the components (A), (C) and optionally (D) and optionally present auxiliary substances (B), such as antioxidants, plasticizers and / or delayed-release auxiliary substances, with the addition of a solvent for which are at least component (C), that is processed for the polymer or polymers (C) to the dosage form.
- Dazu werden die Komponenten (A), ggf. (B), (C) und die ggf. vorhandene Komponente (D) gemischt und die resultierende Formulierungsmischung nach Zugabe des Lösungsmittels und ggf. nach einer Granulierung zu der Darreichungsform geformt. For this purpose, the components are mixed (A), optionally (B), (C) and the optionally present component (D) and molded, the resulting formulation mixture after the addition of the solvent and optionally after granulation to the dosage form.
- Die Mischung der Komponenten (A), ggf. (B), (C) und ggf. (D) erfolgt in einem dem Fachmann bekannten Mischgerät. The mixture of components (A), optionally (B), (C) and optionally (D) takes place in a mixer known to the expert. Das Mischgerät kann beispielsweise ein Wälzmischer, Schüttelmischer, Schermischer oder Zwangsmischer sein. The mixer can be for example a roll mixer, shaking, shear mixer or compulsory mixer.
- Die Zugabe des Lösungsmittels für das Polymere (C) erfolgt zumindest in solchen Mengen, das die Formulierungsmischung gleichmäßig befeuchtet wird. The addition of the solvent for the polymer (C) is effected at least in amounts such that the formulation mixture is moistened evenly.
- Als Lösungsmittel für das Polymere (C) eignen sich vorzugsweise wässrige Lösungsmittel, wie Wasser, Mischungen von Wasser und aliphatischen Alkoholen, vorzugsweise Alkoholen mit C1 bis C6, Estern, Ethern, Kohlenwasserstoffen, besonders bevorzugt destilliertes Wasser, kurzkettige Alkohole, wie Methanol, Ethanol, Isopropanol, Butanol oder wässrige Alkohollösungen. As a solvent for the polymer (C) is preferably an aqueous solvent such as water, mixtures of water and aliphatic alcohols, preferably alcohols with C1 to C6, esters, ethers, hydrocarbons are suitable, more preferably distilled water, short chain alcohols, such as methanol, ethanol, isopropanol, butanol or aqueous alcohol solutions.
- Die Zugabe des Lösungsmittels erfolgt vorzugsweise unter Rühren. The addition of the solvent is preferably carried out with stirring. Anschließend wird die gleichmäßig befeuchtete Masse getrocknet. Subsequently, the uniformly moistened mass is dried. Die Trocknung erfolgt vorzugsweise unter Wärmeeinwirkung bei Temperaturen, bei denen eine Verfärbung der Masse ausgeschlossen werden kann. The drying preferably takes place under the action of heat at temperatures at which discoloration of the composition can be excluded. Durch einfache Vorversuchte ist diese Temperatur feststellbar. By simple preliminary this temperature is detected.
- Vor oder nach der Trocknung kann die Masse auf Teilmassen aufgeteilt werden, die vorzugsweise jeweils der Masse einer Einheit der Darreichungsform entsprechen. Before or after drying, the mass may be divided into partial masses, which preferably correspond to the mass of a unit of the dosage form. Die entsprechend getrockneten Massen werden dann zu der Darreichungsform geformt. The appropriately dried materials are then formed into the dosage form.
- Vorzugsweise geschieht dies unter Einsatz von Tablettenpressen. This is preferably done using tablet presses.
- Es ist auch möglich, die Befeuchtung der Formulierungsmischung so durchzuführen, dass vor der Zugabe des Lösungsmittels die Formulierungsmischung, vorzugsweise in Formen auf Teilmassen verteilt, in einem flüssigen Dispergierungsmittel unter Rühren zu dispergieren und dann das Lösungsmittel zuzugeben. It is also possible to perform the moistening of the formulation mixture, that the formulation mixture, preferably distributed before the addition of the solvent in forms part compositions to be dispersed in a liquid dispersant with stirring and then add the solvent. Die Komponente (C) ist in dem Dispergiermittel nicht löslich, das mit dem Lösungsmittel mischbar sein muss. The component (C) is not soluble in the dispersant, which must be miscible with the solvent.
- Als Dispergiermittel eignen sich vorzugsweise hydrophile Lösungsmittel, wie aliphatische Alkohole, Ketone, Ester. As dispersing agents are preferably hydrophilic solvents such as aliphatic alcohols, ketones, esters are suitable. Kurzkettige Alkohole werden bevorzugt eingesetzt. Short-chain alcohols are preferably used.
- Alternativ kann die Befeuchtung der Formulierungsmischung auch so erfolgen, dass das Lösungsmittel als Schaum in die Formulierungsmischung eingearbeitet wird. Alternatively, the humidification of the formulation mixture may also be effected so that the solvent is incorporated as the foam in the formulation mixture. Vorzugsweise wird ein solcher Schaum des Lösungsmittels mit Hilfe hochtouriger Mixer, vorzugsweise unter Zugabe üblicher Schaumstabilisatoren, hergestellt. Preferably, such foam of the solvent with the help of high-speed mixer, preferably prepared by addition of conventional foam stabilizers. Beispielsweise eignen sich als Stabilisatoren hydrophile Polymere wie zB Hydroxypropylmethylcellulose. For example, suitable as stabilizers, hydrophilic polymers such as hydroxypropylmethylcellulose.
- Vorzugsweise wird auch der Schaum unter Rühren in die Formulierungsmischung eingearbeitet, wodurch vorzugsweise eine granulierte Masse erhalten wird. Preferably, the foam preferably with stirring thereby obtain a granulated mass is incorporated into the formulation mixture.
- Die granulierte Masse wird vor oder nach ihrer Aufteilung in Teilmassen, die vorzugsweise der Masse einer Einheit der Darreichungsform entspricht, getrocknet und anschließend zur Darreichungsform geformt. The granulated mass is dried before or after division into sub-compositions which preferably corresponds to the mass of a unit of the dosage form and then shaped into the dosage form.
- Die Trocknung und Formung kann vorzugsweise wie vorstehend angegeben erfolgen. The drying and shaping can preferably be carried out as stated above. Das erfindungsgemäße Verfahren kann auch so durchgeführt werden, dass zu der Formulierungsmischung soviel Lösungsmittel zugegeben wird, dass eine formbare Paste entsteht. The inventive method can also be carried out so that as much solvent is added to the formulation mixture to a moldable paste.
- Eine solche Paste kann vor oder nach ihrer Trocknung, die wie vorstehend aufgeführt, durchgeführt werden kann, in Teilmassen aufgeteilt werden und die getrockneten Massen gegebenenfalls nach einer weiteren Verteilung jeweils auf eine Masse entsprechend der Masse einer Einheit der Darreichungsform zur Darreichungsform geformt oder umgeformt werden. Such a paste may be performed before or after drying, which as noted above, be divided into partial masses and the dried compositions are optionally shaped according to a further distribution in each case on a mass corresponding to the mass of a unit of the dosage form to dosage form or reshaped.
- Dabei ist es möglich, die Teilmassen in Form von Strängen auszubilden, die mit Hilfe eines Siebes oder eines Strangformers erzeugt werden können. It is possible to form the partial masses in the form of strands which can be generated by means of a sieve or a Strangformers. Die getrockneten Stränge werden vorzugsweise vereinzelt und zur Darreichungsform geformt. The dried strands are preferably singulated and formed into the dosage form. Diese Formung erfolgt vorzugsweise mit Hilfe einer Tablettenpresse, unter Einsatz von Formwalzen oder mit Walzen ausgerüsteten Formbändern. This molding is preferably performed with the aid of a tablet press using forming rolls or rolls equipped shaped strips.
- Es ist auch möglich, die Paste zu einem flächenförmigen Gebilde zu verarbeiten und aus dem getrockneten Gebilde die Darreichungsform zu stanzen. It is also possible to process the paste into a sheet-like structure and to punch the dosage form from the dried structure.
- Vorteilhafterweise wird die Paste mit Hilfe eines Extruders verarbeitet, wobei je nach Gestaltung der Extrusion diese Stränge oder flächenförmigen Gebilde erzeugt werden, die durch Abschlagen oder Schneiden bzw. Stanzen vereinzelt werden. Advantageously, the paste is processed by means of an extruder, said strands or sheet-like structures are produced, depending on the design of the extrusion, which are singulated by chopping or cutting or punching. Die vereinzelten Teilmassen können wie vorstehend ausgeführt zu der Darreichungsform geformt, verformt oder ausgestanzt werden. The separated part mass can be molded, formed or punched into the dosage form as stated above. Entsprechende Vorrichtungen sind dem Fachmann bekannt. Corresponding devices are known in the art.
- Dabei kann das erfindungsgemäße Verfahren kontinuierlich oder diskontinuierlich durchgeführt werden. In this case, the inventive method can be performed continuously or batchwise.
- Es ist auch möglich, zu der Formulierungsmischung soviel Lösungsmittel zuzugeben, dass zumindest die Polymerkomponente (C) gelöst wird. It is also possible to add so much solvent to the formulation mixture, that at least the polymer component is dissolved (C). Eine solche Lösung oder Dispersion/Suspension wird vorzugsweise zu einem flächenförmigen Gebilde verarbeitet, wobei bevorzugt ein Extruder mit einer Flachdüse zum Einsatz kommt oder die Lösung auf eine flächenförmige, ebene Unterlage ausgegossen wird. Such a solution or dispersion / suspension is preferably processed into a sheet-like structure, wherein preferably an extruder with a flat die is used, or the solution is poured out onto a sheet-like, flat surface.
- Nach Trocknung, wie vorstehend angegeben, können aus den flächenförmigen Gebilden die Darreichungsformen durch Stanzen oder Kalandrieren erhalten werden. After drying, as indicated above, the dosage forms may be obtained by stamping or calendering of the sheet-like structures. Es ist auch möglich, die Lösung, wie vorstehend angegeben, zu Strängen zu verarbeiten und diese, bevorzugt nach ihrer Trocknung, zu vereinzeln und zur Darreichungsform zu formen. It is also possible to process the solution as indicated above to form extrudates and these, preferably after drying to separate, and to form the dosage form.
- Alternativ kann die Lösung auch in solchen Teilmengen aufgeteilt werden, dass sie nach dem Trocknen jeweils der Masse einer Einheit der Darreichungsform entspricht, wobei vorzugsweise dafür bereits Formen entsprechend der Form einer Einheit der Darreichungsform eingesetzt werden. Alternatively, the solution can also be divided into subsets such that, after drying them respectively corresponds to the mass of a unit of the dosage form, said forms already be used according to the shape of a unit of the dosage form, preferably for it.
- Sofern die Lösung in beliebige Teilmengen aufgeteilt wird, können die Teilmengen nach dem Trocknen gegebenenfalls wieder vereinigt und zu der Darreichungsform geformt werden, wie z. Provided that the solution is divided into arbitrary subsets, the subsets can be optionally recombined after drying and formed into the dosage form, such as. B. in eine Kapsel abgefüllt oder zu einer Tablette verpresst werden. For example, be filled into a capsule or compressed into a tablet.
- Vorzugsweise werden die mit Lösungsmittel versetzten Formulierungsmischungen bei Temperaturen von 20°C bis 40°C verarbeitet, wobei außer bei der Trocknung zur Entfernung des Lösungsmittels und des ggf. vorhandenen Dispergierungsmittels keine höheren Temperaturen angewendet werden. Preferably, the offset with solvent mixtures formulation are processed at temperatures of 20 ° C to 40 ° C, except for the drying to remove the solvent and the dispersant may be present no higher temperature can be employed. Die Temperatur zum Trocknen muss unterhalb der Zersetzungstemperatur der Komponenten gewählt werden. The temperature for drying must be selected below the decomposition temperature of the components. Gegebenenfalls kann nach der Formgebung zur Darreichungsform nochmals eine Trocknung entsprechend der vorstehend beschriebenen Trocknung erfolgen. Optionally, a drying according to the above-described drying can be carried out again after the shaping to the dosage form.
- Es sind auch Kombinationen einzelner Verfahrensschritte der vorstehenden Verfahrensvarianten möglich, um die erfindungsgemäße Darreichungsform herzustellen. There are also combinations of individual steps of the above process variants are possible to produce the dosage form.
- Die erfindungsgemäße Darreichungsform weist eine kontrollierte Freisetzung des Wirkstoffes auf. The inventive dosage form comprises a controlled release of the active ingredient. Sie eignet sich dabei vorzugsweise für eine 2x tägliche Verabreichung an Patienten. It is preferably suitable for a 2x daily administration to patients.
- Die erfindungsgemäße Darreichungsform kann einen oder mehrere Substanzen (A) zumindest teilweise in einer darüber hinaus retardierten Form aufweisen, wobei die Retardierung mit Hilfe von üblichen, dem Fachmann bekannten Materialien und Verfahren erzielt werden kann, beispielsweise durch Einbetten der Substanz in eine retardierende Matrix oder durch das Aufbringen eines oder mehrerer retardierender Überzüge. The dosage form according to the invention may comprise one or more substances (A) at least partially in a moreover retarded form, wherein the retardation with the aid of customary processes known to the person skilled in materials and methods can be achieved, for example by embedding the substance in a delayed-release matrix or by applying one or more delayed-release coatings. Die Substanzfreisetzung muss aber so gesteuert sein, daß durch die Zugabe von retardierenden Materialien keine Beeinträchtigung der notwendigen Härte erfolgt. but the substance release must be controlled so that by the addition of retarding materials are not impair the necessary hardness.
- Die kontrollierte Freisetzung aus der erfindungsgemäßen Darreichungsform wird vorzugsweise durch Einbettung der Substanz in eine Matrix erzielt. The controlled release from the dosage form according to the invention is preferably achieved by embedding the substance in a matrix. Die als Matrixmaterialien dienenden Hilfsstoffe kontrollieren die Freisetzung. The serving as matrix materials control the release excipients. Matrixmaterialien können beispielweise hydrophile, gelbildende Materialien sein, woraus die Freisetzung hauptsächlich durch Diffusion erfolgt, oder hydrophobe Materialien, woraus die Freisetzung hauptsächlich durch Diffusion aus den Poren in der Matrix erfolgt. Matrix materials may, for example, be hydrophilic, gel-forming materials, from which release proceeds mainly by diffusion, or hydrophobic materials, from which release proceeds mainly by diffusion from the pores in the matrix.
- Als Matrixmaterialien können physiologisch verträgliche, hydrophile Materialien verwendet werden, welche dem Fachmann bekannt sind. Matrix materials physiologically acceptable, hydrophobic materials can be used, which are known in the art. Vorzugsweise werden als hydrophile Matrixmaterialien Polymere, besonders bevorzugt Celluloseether, Celluloseester und/oder Acrylharze verwendet. Preferably cellulose ethers, Celluloseester and / or acrylic resins are used as hydrophilic matrix materials are polymers, especially preferably used. Ganz besonders bevorzugt werden als Matrixmaterialien Ethylcellulose, Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Hydroxymethylcellulose, Poly(meth)acrylsäure und/oder deren Derivate, wie deren Salze, Amide oder Ester eingesetzt. are very particularly preferred as matrix materials ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly (meth) acrylic acid and / or their derivatives such as their salts, amides or esters.
- Ebenfalls bevorzugt sind Matrixmaterialien aus hydrophoben Materialien, wie hydrophoben Polymeren, Wachsen, Fetten, langkettigen Fettsäuren, Fettalkoholen oder entsprechenden Estern oder Ethern oder deren Gemische. Also preferred are matrix materials made of hydrophobic materials such as hydrophobic polymers, waxes, fats, long chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof. Besonders bevorzugt werden als hydrophobe Materialien Mono- oder Diglyceride von C12-C30-Fettsäuren und/oder C12-C30-Fettalkohole und/oder Wachse oder deren Gemische eingesetzt. Particularly preferred hydrophobic materials mono- or diglycerides of C12-C30 fatty acids and / or C12-C30 fatty alcohols and / or waxes or mixtures thereof.
- Es ist auch möglich, Mischungen der vorstehend genannten hydrophilen und hydrophoben Materalien als Matrixmaterialien einzusetzen. It is also possible to use mixtures of the above hydrophilic and hydrophobic material is as matrix materials.
- Des weiteren können auch die Komponenten (C) und ggf. vorhandene Komponente (D), die zur Erzielung der erfindungsgemäß notwendigen Bruchfestigkeit von mindestens 400 N dienen, bereits als zusätzliche Matrixmaterialien dienen. Further, the components (C) and optionally present component (D), which serve to achieve the necessary breaking strength according to the invention of at least 400 N, already serve as additional matrix materials.
- Sofern die erfindungsgemäße Darreichungsform zur oralen Applikation vorgesehen ist, kann sie bevorzugt auch einen magensaftresistenten Überzug aufweisen, der sich in Abhängigkeit vom pH-Wert der Freisetzungsumgebung auflöst. If the dosage form according to the invention is intended for oral administration, they can preferably also have an enteric coating which dissolves as a function of the pH value of the release environment. Durch diesen Überzug kann erreicht werden, daß die erfindungsgemäße Darreichungsform den Magentrakt unaufgelöst passiert und der Wirkstoff erst im Darmtrakt zur Freisetzung gelangt. Through this coating can be achieved in that the dosage form passes through the gastric tract undissolved and the active substance reaches the release only in the intestinal tract. Vorzugsweise löst sich der magensaftresistente Überzug bei einem pH-Wert zwischen 5 und 7,5 auf. Preferably, the enteric coating dissolves at a pH-value between 5 and 7.5.
- Entsprechende Materialien und Verfahren zur Retardierung von Wirkstoffen sowie zum Aufbringen magensaftresistenter Überzüge sind dem Fachmann beispielsweise aus „Coated Pharmaceutical Dosage Forms – Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials" von Kurt N. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1. Auflage, 1998, Medpharm Scientific Publishers bekannt. Die entsprechende Literaturbeschreibung wird hiermit als Referenz eingeführt und gilt als Teil der Offenbarung. Corresponding materials and methods for the controlled release of active ingredients and for applying enteric coating to the skilled artisan, for example, "Coated Pharmaceutical Dosage Forms - Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials" by Kurt N. Bauer, K. Lehmann, Hermann P . Osterwaldstraße, Rothgang, Gerhart, 1st edition, 1998, Medpharm Scientific Publishers known. the corresponding literature description is hereby introduced as a reference and is part of the disclosure.
- Bei den erfindungsgemäß erhaltenen Darreichungsformen wird die Bruchfestigkeit nach der aufgeführten Meßmethode bestimmt, wobei von Tabletten abweichende Darreichungsformen ebenso geprüft werden. In the dosage forms according to the invention obtained, the breaking strength is determined using the measurement method mentioned, said different dosage forms of tablets are also tested.
- Zur Ermittlung der Bruchfestigkeit der erfindungsgemäßen Darreichungsform werden Darreichungsformen, bevorzugt Tabletten, mit einem Durchmesser von 10 mm und einer Höhe von 5 mm hergestellt. To determine the breaking strength of the dosage form according to the invention are dosage forms, preferably tablets, having a diameter of 10 mm and a height of 5 mm.
- Mit diesen Darreichungsformen, vorzugsweise Tabletten, wird gemäß der Methode zur Bestimmung der Bruchfestigkeit von Tabletten, veröffentlicht im Europäischen Arzneibuch 1997, Seite 143, 144, Methode Nr. 2.9.8. These dosage forms, preferably tablets, method no. 2.9.8, according to the method for determining the breaking strength of tablets published in the European Pharmacopoeia 1997, page 143, 144. unter Einsatz der nachstehend aufgeführten Apparatur die Bruchfestigkeit der Darreichungsform bestimmt. using the apparatus described below determines the breaking strength of the dosage form. Als Apparatur für die Messung wird eine Zwick Materialprüfmaschine „Zwick Z 2.5", Materialprüfmaschine Fmax 2.5 kN mit einem Traversenweg von max. 1150 mm, der durch einen Aufbau mit Hilfe einer Säule und einer Spindel einzustellen ist, einen freien Arbeitsraum nach hinten von 100 mm und einer zwischen 0,1 bis 800 mm/min. einstellbaren Prüfgeschwindigkeit und einer Software: testControl eingesetzt. Es wird ein Druckstempel mit schraubbaren Einsätzen und einem Zylinder (Durchmesser 10 mm), ein Kraftaufnehmer, Fmax. 1 kN, Durchmesser 8 mm, Klasse 0.5 ab 10 N, Klasse 1 ab 2 N nach ISO 7500-1, mit Hersteller-Prüfzertifikat M nach DIN 55350-18 (Zwick-Bruttokraft Fmax 1,45 kN) zur Messung eingesetzt (alles Apparaturen der Firma Zwick GmbH & Co. KG, Ulm, Deutschland) mit der Bestell-Nr. BTC-FR 2.5 TH. D09 für die Prüfmaschine, der Bestell-Nr. BTC-LC 0050N. P01 für den Kraftaufnehmer, der Bestell-Nr. BO 70000 S06 für die Zentriervorrichtung. The apparatus used for the measurement is a Zwick material tester "Zwick Z 2.5", material testing Fmax = 2.5 kN with a crosshead of max. 1150 mm, which is set by a configuration using a column and a spindle, a free clearance behind of 100 mm ., and a from 0.1 to 800 mm / min test speed adjustable and software. testControl There is a pressure piston with screw-in inserts and a cylinder (diameter 10 mm), a force transducer, Fmax 1 kN, diameter 8 mm, class. 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturer's test certificate M to DIN 55350-18 (Zwick gross force Fmax 1.45 kN) used to measure (all apparatus from Zwick GmbH & Co. KG , Ulm, Germany) with the order no. BTC-FR 2.5 TH. D09 for the tester, order no. BTC-LC 0050N. P01 for the force transducer, order no. BO 70000 S06 for the centering device.
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4 4 zeigt die Messung der Bruchfestigkeit einer Tablette, insbesondere die dafür eingesetzte Justierungsvorrichtung ( shows the measurement of the breaking strength of a tablet, in particular the adjusting device used for this purpose (6 6 ) der Tablette ( () Of the tablet4 4 ) vor und während der Messung. ) Before and during the measurement. Dazu wird die Tablette ( For this, the tablet is (4 4 ) zwischen der oberen Druckplatte ( ) (Between the upper pressure plate1 1 ) und der unteren Druckplatte ( ) And the lower pressure plate (3 3 ) der nicht dargestellten Vorrichtung zur Kraftaufbringung mit Hilfe von zwei 2-teiligen Einspannvorrichtungen, die jeweils mit der oberen bzw. unteren Druckplatte nach Einstellung des zur Aufnahme und zur Zentrierung der zu messenden Tablette notwendigen Abstands ( ) Of the device not shown for the application of force by means of two 2-part clamping devices, which (in each case with the upper and lower printing plate after adjustment of the necessary for receiving and centering the tablet to be measured distance5 5 ) fest verbunden (nicht dargestellt) werden. are not shown)) firmly connected (. Zur Einstellung des Abstands ( (For adjusting the distance5 5 ) können die 2-teiligen Einspannvorrichtungen jeweils auf der Druckplatte, auf der sie gelagert sind, horizontal nach außen oder innen bewegt werden. ), The 2-part clamping devices in each case on the pressure plate on which they are mounted, are moved horizontally outwards or inwards. Die verwendeten Bezugszeichen beziehen sich ausschließlich auf The reference numerals used relate solely to4 4 . , - Als bruchfest bei einer bestimmten Krafteinwirkung werden auch die Tabletten eingestuft, bei denen kein Bruch feststellbar, aber ggf. eine plastische Verformung der Tablette durch die Krafteinwirkung erfolgt ist. As resistant to breaking under a specific load, the tablets are classified, which have not broken but possibly plastic deformation of the tablet is made by the application of force.
- Im folgenden wird die Erfindung anhand von Beispielen erläutert. In the following the invention is explained by examples. Diese Erläuterungen sind lediglich beispielhaft und schränken den allgemeinen Erfindungsgedanken nicht ein. These explanations are merely exemplary and do not restrict the general inventive idea.
- In einer Reihe von Beispielen wurden Diltiazem Hydrochlorid, Verapamil Hyddrochlorid und Carbamazepin als Wirkstoffe (Substanz (A)) verwendet. In a series of examples diltiazem hydrochloride, verapamil Hyddrochlorid carbamazepine and as active ingredients (substance (A)) were used.
- Alle Komponenten wurden in einem Freifallmischer gemischt. All components were mixed in a tumbler. Ein Tablettierwerkzeug mit Oberstempel, Unterstempel und Matrize für Tabletten mit 10 mm Durchmesser und einem Wölbungsradius von 8 mm wurde in einem Heizschrank auf 80°C erhitzt. A tabletting tool with top punch, bottom punch and die for tablets with 10 mm diameter and a radius of curvature of 8 mm was heated in an oven at 80 ° C. Mittels des erhitzten Werkzeugs wurden jeweils 300 mg der Pulvermischung verpresst, wobei der Pressdruck für mindestens 15 s aufrechterhalten wurde durch Einspannen des Tablettierwerkzeugs in einen Schraubstock. By means of the heated tool in each case 300 mg of the powder mixture were pressed, wherein the pressing pressure for at least 15 s is maintained by clamping the tabletting tool in a vice.
- Die Bruchfestigkeit der Tabletten wurde gemäß der angegebenen Methode mit der angegebenen Apparatur bestimmt. The hardness of the tablets was determined according to the method specified with the stated apparatus. Bei einer Krafteinwirkung von 500 N trat kein Bruch der Tabletten auf. With a force of 500 N no break the tablets did.
- Die Tablette konnte mit einem Hammer nicht zerkleinert werden. The tablet could not be comminuted using a hammer. Dies war auch mit Hilfe von Mörser und Pistill nicht möglich. This was not possible with the aid of a mortar and pestle.
- Die in-vitro-Freisetzung des Wirkstoffs aus der Zubereitung wurde in der Blattrührerapparatur nach Pharm. Eur. Bestimmt (Paddle mit Sinker). The in vitro release of the active ingredient from the preparation was determined in a paddle stirrer according to Pharm. Eur. (Paddle with sinker). Die Temperatur des Freisetzungsmediums betrug 37°C und die Umdrehungsgeschwindigkeit des Rührers 50 min -1 . The temperature of the release medium was 37 ° C and the rotational speed of the stirrer 50 min -1. Zu Beginn der Untersuchung wurde jede Tablette in jeweils 900 ml künstlichen Magensaft pH 1,2 gegeben. At the beginning of the examination, each tablet was placed in each 900 ml of artificial gastric juice pH 1.2. Nach 30 Minuten wurde durch Zugabe von Lauge der pH-Wert auf 2,3 erhöht, nach weiteren 90 Minuten auf pH 6,5 und nach nochmals 60 weiteren Minuten auf pH 7,2. After 30 minutes the pH was increased to 2.3 by addition of alkali, after a further 90 minutes to pH 6.5 and after a further 60 minutes to pH 7.2. Die jeweils zu einem Zeitpunkt im Lösungsmedium befindliche freigesetzte Menge des Wirkstoffs wurde spektralphotometrisch bei 236 nm in 2 mm Küvetten bestimmt. The located one at a time in the dissolution medium released amount of the drug was measured spectrophotometrically at 236 nm in 2 mm cuvettes.
- Beispiel 2: Example 2:
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- Die Bruchfestigkeit der Tabletten wurde gemäß der angegebenen Methode mit Hilfe der angegebenen Apparatur bestimmt. The hardness of the tablets was determined according to the method specified with the stated apparatus. Bei einer Krafteinwirkung von 500 N trat kein Bruch der Tabletten auf. With a force of 500 N no break the tablets did.
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- Beispiel 3: Example 3:
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- Die Bruchfestigkeit der Tabletten wurde gemäß der angegebenen Methode mit Hilfe der angegebenen Apparatur bestimmt. The hardness of the tablets was determined according to the method specified with the stated apparatus. Bei einer Krafteinwirkung von 500 N trat kein Bruch der Tabletten auf. With a force of 500 N no break the tablets did.
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Claims (15)
- Darreichungsform umfassend – eine physiologisch wirksame Substanz (A) mit zumindest teilweise retardierter Freisetzung; Dosage form comprising - a physiologically active substance (A) with at least partially retarded release; – gegebenenfalls einen oder mehrere physiologisch verträgliche Hilfsstoffe (B); - optionally one or more physiologically acceptable auxiliary substances (B); und – ein synthetisches oder natürliches Polymer (C); and - a synthetic or natural polymer (C); wobei die Darreichungsform eine Bruchfestigkeit von mindestens 400 N aufweist. wherein the dosage form exhibits a breaking strength of at least 400 N.
- Darreichungsform nach Anspruch 1, dadurch gekennzeichnet, dass sie keine psychotrop wirkende Substanz enthält. Dosage form according to claim 1, characterized in that it contains no psychotropic active substances.
- Darreichungsform nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass sie ein natürliches, halbsynthetisches oder synthetisches Wachs (D) enthält. Dosage form according to claim 1 or 2, characterized in that it contains a natural, semisynthetic or synthetic wax (D).
- Darreichungsform nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass die Substanz (A) ein Nahrungsergänzungsmittel oder ein Arzneistoff ist. Dosage form according to any of the preceding claims, characterized in that the substance (A) is a food supplement or a drug.
- Darreichungsform nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass sie in Form einer Tablette vorliegt. Dosage form according to any of the preceding claims, characterized in that it is in the form of a tablet.
- Darreichungsform nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass sie in multipartikulärer Form; Dosage form according to any of the preceding claims, characterized in that it is in multiparticulate form; vorzugsweise in Form von Mikrotabletten, Mikropellets, Granulaten, Sphäroiden, Perlen oder Pellets, gegebenenfalls zu Tabletten verpresst oder in Kapseln abgefüllt, vorliegt. preferably, optionally pressed or in the form of microtablets, micropellets, granules, spheroids, beads or pellets into tablets filled in capsules, is present.
- Darreichungsform nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass das Polymer (C) ausgewählt ist aus der Gruppe bestehend aus Polymethylenoxid, Polyethylenoxid, Polypropylenoxid, Polyethylen, Polypropylen, Polyvinylchlorid, Polycarbonat, Polystyrol, Polyacrylat, deren Copolymerisaten, und deren Mischungen. Dosage form according to any of the preceding claims, characterized in that the polymer is selected (C) from the group consisting of polymethylene oxide, polyethylene oxide, polypropylene oxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers thereof, and mixtures thereof.
- Darreichungsform nach Anspruch 7, dadurch gekennzeichnet, dass das Polymer (C) ein Molekulargewicht von mindestens 0,5 10 6 g/mol, bevorzugter mindestens 1,0 10 6 g/mol und noch bevorzugter 1,0 10 6 bis 15 10 6 g/mol aufweist. Dosage form according to claim 7, characterized in that the polymer (C) has a molecular weight of at least 0.5 10 6 g / mol, more preferably at least 1.0 10 6 g / mol and more preferably 1.0 10 6 to 15 10 6 g / mol.
- Darreichungsform nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass sie wenigstens ein Wachs (D) mit einem Erweichungspunkt von mindestens 50°C umfasst. Dosage form according to any of the preceding claims, characterized in that it comprises at least one wax (D) having a softening point of at least 50 ° C.
- Darreichungsform nach Anspruch 9, dadurch gekennzeichnet, dass das Wachs (D) Carnaubawachs oder Bienenwachs ist. Dosage form according to claim 9, characterized in that the wax (D) Carnauba wax or bees wax.
- Darreichungsform nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass die Substanz (A) in einer Retardmatrix vorliegt. Dosage form according to any of the preceding claims, characterized in that the substance (A) is in a sustained release matrix.
- Darreichungsform nach Anspruch 11, dadurch gekennzeichnet, dass das Polymer (C) und/oder das gegebenenfalls vorhandene Wachs (D) als Retardmatrixmaterial dient. Dosage form according to claim 11, characterized in that the polymer (C) and / or the optional wax (D) serves as Retardmatrixmaterial.
- Darreichungsform nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass sie unter physiologischen Bedingungen nach 5 Stunden höchstens 99% der Substanz (A) freisetzt. Dosage form according to any of the preceding claims, characterized in that it releases under physiological conditions after 5 hours of not more than 99% of the substance (A).
- Darreichungsform nach Anspruch 13, dadurch gekennzeichnet, dass sie weder Tramadol Hydrochlorid noch Oxycodon Hydrochlorid enthält. Dosage form according to claim 13, characterized in that it does not contain either tramadol hydrochloride oxycodone hydrochloride.
- Darreichungsform nach einem der vorstehenden Ansprüche, dadurch gekennzeichnet, dass die Substanz (A) ein Arzneistoff ist, ausgewählt aus der Gruppe bestehend aus Mitteln zur Behandlung und Vorbeugung von Erkrankungen des alimentären Systems und Stoffwechsels; Dosage form according to any of the preceding claims, characterized in that the substance (A) is a drug selected from the group consisting of agents for the treatment and prevention of diseases of the digestive system and metabolism; Mitteln zur Behandlung und Vorbeugung von Erkrankungen des Bluts und der blutbildenden Organe; Agents for the treatment and prevention of diseases of the blood and blood-forming organs; Mitteln zur Behandlung und Vorbeugung von Erkrankungen des kardiovaskulären Systems; Agents for the treatment and prevention of diseases of the cardiovascular system; Dermatika; Dermatological; Mitteln zur Behandlung und Vorbeugung von Erkrankungen des Urogenitalsystems und Sexualhormonen; Agents for the treatment and prevention of diseases of the genitourinary system and sex hormones; systemischen Hormonpräparaten ausschließlich Sexualhormonen und Insulinen; systemic hormone preparations exclusively sex hormones and insulins; Antiinfektiva zur systemischen Anwendung; Anti-infectives for systemic use; antineoplastischen und immunmodulierenden Mitteln; antineoplastic and immunomodulatory agents; Mitteln zur Behandlung und Vorbeugung von Erkrankungen der Muskeln und des Skelettsystems; Agents for the treatment and prevention of diseases of the muscles and the skeletal system; Mitteln zur Behandlung und Vorbeugung von Erkrankungen des Nervensystems; Agents for the treatment and prevention of diseases of the nervous system; antiparasitären Mitteln, Insektiziden und Repellenzien; antiparasitic agents, insecticides and repellents; Mitteln zur Behandlung und Vorbeugung von Erkrankungen des Respirationstrakts; Agents for the treatment and prevention of diseases of the respiratory tract; Mitteln zur Behandlung und Vorbeugung von Erkrankungen der Sinnesorgane; Agents for the treatment and prevention of diseases of the sense organs; Allgemeinen Diätetika und Radiotherapeutika. General diet and radiotherapeutic agents.
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DE102005005446A DE102005005446A1 (en) | 2005-02-04 | 2005-02-04 | Unbreakable dosage forms with delayed release |
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CN2006800113003A CN101175482B (en) | 2005-02-04 | 2006-02-06 | Abuse-proofed dosage form |
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ES12001792.6T ES2651016T3 (en) | 2005-02-04 | 2006-02-06 | Dosage forms resistant to breakage delayed release |
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PT120017926T PT2478896T (en) | 2005-02-04 | 2006-02-06 | Fracture-resistant application forms with delayed release |
PE2006000142A PE10872006A1 (en) | 2005-02-04 | 2006-02-06 | tear resistant dosage forms with sustained release |
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US12/140,665 US8192722B2 (en) | 2003-08-06 | 2008-06-17 | Abuse-proof dosage form |
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RU2010119291/15A RU2461381C2 (en) | 2005-02-04 | 2010-05-14 | Degradation-resistant dosage form with delayed release of oxycodone hydrochloride |
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US14/138,372 US20140170079A1 (en) | 2003-08-06 | 2013-12-23 | Abuse-proofed dosage form |
US14/141,793 US20140112984A1 (en) | 2005-02-04 | 2013-12-27 | Crush resistant delayed-release dosage forms |
US14/324,366 US20140322311A1 (en) | 2005-02-04 | 2014-07-07 | Crush resistan delayed-release dosage form |
US14/749,939 US20150290138A1 (en) | 2005-02-04 | 2015-06-25 | Crush resistant delayed-release dosage forms |
US14/848,457 US20150374630A1 (en) | 2005-02-04 | 2015-09-09 | Crush resistant delayed-release dosage forms |
US14/875,007 US20160022587A1 (en) | 2003-08-06 | 2015-10-05 | Abuse-proofed dosage form |
US14/994,691 US20160120810A1 (en) | 2005-02-04 | 2016-01-13 | Crush resistant delayed-release dosage forms |
US15/061,252 US20160184297A1 (en) | 2005-02-04 | 2016-03-04 | Crush resistant delayed-release dosage forms |
US15/132,325 US9629807B2 (en) | 2003-08-06 | 2016-04-19 | Abuse-proofed dosage form |
US15/459,180 US10058548B2 (en) | 2003-08-06 | 2017-03-15 | Abuse-proofed dosage form |
ARP170100751A AR107985A2 (en) | 2005-02-04 | 2017-03-27 | Formulations resistant to breakage sustained release |
HRP20170746TT HRP20170746T1 (en) | 2005-02-04 | 2017-05-18 | Break-resistant delayed-release forms of administration |
CY20171100553T CY1118914T1 (en) | 2005-02-04 | 2017-05-29 | RESISTANT FORMS dosologisis to breakage by retarding release |
US15/649,880 US20170312271A1 (en) | 2005-02-04 | 2017-07-14 | Crush resistant delayed-release dosage forms |
HRP20171695TT HRP20171695T1 (en) | 2005-02-04 | 2017-11-06 | Fracture-resistant application forms with delayed release |
CY20171101186T CY1119598T1 (en) | 2005-02-04 | 2017-11-14 | RESISTANT FORMS dosologisis to breakage by retarding release |
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US16/032,467 US20190008849A1 (en) | 2003-08-06 | 2018-07-11 | Abuse-proofed dosage form |
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